Caffeine Modulates Tau Phosphorylation and Affects Akt Signaling in Postmitotic Neurons

Neuronal cell cycle reentry, which is associated with aberrant tau phosphorylation, is thought to be a mechanism of neurodegeneration in AD. Caffeine is a neuroprotective drug known to inhibit the cell cycle, suggesting that its neuroprotective nature may rely, at least in part, on preventing tau abnormalities secondary to its inhibitory effect on neuronal cell cycle-related pathways. Accordingly, we have explored in the present study the impact of caffeine on cell cycle-linked parameters and tau phosphorylation patterns in an attempt to identify molecular clues to its neuroprotective effect. We show that caffeine blocks the cell cycle at G1 phase in neuroblastoma cells and leads to a decrease in tau phosphorylation; similarly, exposure of postmitotic neurons to caffeine led to changes in tau phosphorylation concomitantly with downregulation of Akt signaling. Taken together, our results show a unique impact of caffeine on tau phosphorylation and warrant further investigation to address whether caffeine may help prevent neuronal death by preventing tau abnormalities secondary to aberrant entry into the cell cycle.     

Aconitin

Ohne ZusammenfassungDieser Aufsatz lag schon ganz zum Drucke bereit, als wir die gründliche Abhandlung des Herrn Schroff über Aconitum erhielten. Manche beobachtete, bis dahin vereinzelt stehende Symptome erhielten durch seine Versuche eine ergänzende Erläuterung. Einige von uns angestellte Versuche dagegen setzen uns in Stand, dann und wann zu sehr generalisirte Angaben des Herrn Schroff zu berichtigen. — Im Ganzen freute es uns also sehr, diese Arbeit noch eben zeitig genug empfangen zu haben, um unsre Schlüsse danach einzurichten. Um so mehr freute uns dieser Aufsatz aber, weil das Resultat der darin enthaltenen Versuche grösstentheils die Richtigkeit der unsrigen bestätigt. und dabei der Kopf geschüttelt, wie um eine unangenehme dort gefühlte Empfindung zu entfernen. Die Respiration ist beschleunigt und keuchend. — Nach 8 Minuten sinkt das Thier auf die rechte Seite und zeigt eine schwache, träge Respiration. — Nach 11 Minuten entstehen klonische Krämpfe in den Füssen, dem Schwanz und dem Hals. Die Respiration ist schwach. — Nach 13 Minuten wird keine Respiration mehr beobachtet. Nur zeigen sich noch von Zeit zu Zeit Zuckungen im Schwanze und in den Flügeln. — Nach 16 Minuten wird keine Bewegung gesehen, und das Herz steht bei der Oeffnung des Thorax still.Bei der Autopsie wird in den Hirnhäuten viel Blut gefunden. Das Gehirn enthält ein normales Quantum Blut. Das Herz ist mit geronnenem Blute überfüllt. Der Drüsenmagen ist einigermaassen höher roth als der zweite Magen. Sonst aber wird nichts Abnormes angetroffen.     

Decreased α event-related synchronization in the left posterior temporal cortex in schizophrenia: a magnetoencephalography-beamformer study

Alpha rhythm is one of the most prominent electromagnetic changes in the brain, and electroencephalography (EEG) alpha reactivity disturbance may sometimes represent an early sign of cerebral dysfunction. Although magnetoencephalography (MEG) has a better spatial resolution than EEG, it has not extensively been used to explore alpha-power change deficits in schizophrenia as a possible neurophysiological marker of the disease. The purpose of this study was to use MEG to identify abnormalities in alpha synchronization induced by eye-closing in schizophrenia patients compared to healthy controls, and to investigate whether alpha reactivity deficits correlate with clinical features of the disorder. MEG data were recorded in 22 schizophrenia patients and 20 age- and gender-matched controls during eyes-open/eyes-closed resting states. Cortical sources of event-related synchronization (ERS) were estimated using multiple source beamformer, and BrainVoyager was used for statistic group analysis. A significant decrease in ERS in the upper alpha band (10–13 Hz) was found in the left posterior temporal region in schizophrenia patients relative to controls, and this activity showed correlation with visual memory scores. This upper alpha ERS deficit may indicate left temporal dysfunction and visual-information processing impairment in schizophrenia, and upon further confirmation it might represent a neurophysiological state marker of the disorder.     

Psychopathology and working memory-induced activation of the prefrontal cortex in schizophrenia-like psychosis of epilepsy: Evidence from magnetoencephalography

Aim: The aim of this study was to investigate whether magnetoencephalographic oscillations underlying working memory dysfunction in the dorsolateral prefrontal cortex (DLPFC) are related to psychopathological disturbance in patients with schizophrenia‐like psychosis of epilepsy (SLPE). Methods: Twelve patients with SLPE and 14 non‐psychotic epilepsy controls participated in this study. Magnetoencephalography was recorded while patients performed a visual working memory (WM) task. Psychopathology was assessed using a four‐factor structure of the Brief Psychiatric Rating Scale, and regression analyses were carried out to examine the relative impact of severity of psychopathology on WM‐induced activation of the DLPFC. Results: We found that activation of the WM‐compromising DLPFC, as indicated by increased alpha desynchronization in patients with SLPE compared with their non‐psychotic counterparts, showed a positive linear correlation with disorganization symptom scores. This association remained significant after controlling for confounding factors, including age, task performance, IQ, and duration of psychosis. Conclusion: Our results indicate that abnormal activation in prefrontal areas engaged during working memory may be critical to domains of psychopathology, in particular disorganized thought‐processing in patients with SLPE.     

Induced oscillatory responses during the Sternberg's visual memory task in patients with Alzheimer's disease and mild cognitive impairment

In this study we used magnetoencephalography during a modified version of the Sternberg's memory recognition task performed by patients with early Alzheimer's disease (AD), mild cognitive impairment (MCI), and by age-matched healthy controls to identify differences in induced oscillatory responses. For analyses, we focused on the retention period of the working memory task. Multiple-source beamformer and Brain Voyager were used for localization of source-power changes across the cortex and for statistic group analyses, respectively. We found significant differences in oscillatory response during the task, specifically in beta and gamma frequency bands: patients with AD showed reduced beta event-related desynchronization (ERD) in the right central area compared to controls, and reduced gamma ERD in the left prefrontal and medial parietal cortex compared to patients with MCI. Our findings suggest that reduced oscillatory responses over certain brain regions in high frequency bands (i.e., beta, gamma), and especially in the beta band that was significantly different between AD patients and healthy subjects, may represent brain electromagnetic changes underlying visual-object working memory dysfunction in early AD, and a neurophysiological indicator of cognitive decline.     

Delphinin

Ohne Zusammenfassung     

Predictive factors of occupational noise-induced hearing loss in Spanish workers: A prospective study

The purpose of our study was to identify the main factors associated with objective noise-induced hearing loss (NIHL), as indicated by abnormal audiometric testing, in Spanish workers exposed to occupational noise in the construction industry. We carried out a prospective study in Tenerife, Spain, using 150 employees exposed to occupational noise and 150 age-matched controls who were not working in noisy environments. The variables analyzed included sociodemographic data, noise-related factors, types of hearing protection, self-report hearing loss, and auditory-related symptoms (e.g., tinnitus, vertigo). Workers with pathological audiograms had significantly longer noise-exposure duration (16.2 ± 11.4 years) relative to those with normal audiograms (10.2 ± 7.0 years; t = 3.99, P < 0.001). The vast majority of those who never used hearing protection measures had audiometric abnormalities (94.1%). Additionally, workers using at least one of the protection devices (earplugs or earmuffs) had significantly more audiometric abnormalities than those using both protection measures simultaneously (Chi square = 16.07; P < 0.001). The logistic regression analysis indicates that the use of hearing protection measures [odds ratio (OR) = 12.30, confidence interval (CI) = 4.36-13.81, P < 0.001], and noise-exposure duration (OR = 1.35, CI = 1.08-1.99, P = 0.040) are significant predictors of NIHL. This regression model correctly predicted 78.2% of individuals with pathological audiograms. The combined use of hearing protection measures, in particular earplugs and earmuffs, associates with a lower rate of audiometric abnormalities in subjects with high occupational noise exposure. The use of hearing protection measures at work and noise-exposure duration are best predictive factors of NIHL. Auditory-related symptoms and self-report hearing loss do not represent good indicators of objective NIHL. Routine monitoring of noise levels and hearing status are of great importance as part of effective hearing conservation programs.     

Frontal shift of posterior alpha activity is correlated with cognitive impairment in early Alzheimer's disease: A magnetoencephalography–beamformer study

Background: Induced‐oscillatory activity is considered a key factor for understanding functional processes in the brain. Magnetoencephalography (MEG) can measure oscillatory activity non‐invasively with higher spatial resolution than electroencephalography (EEG). However, MEG has rarely been used to explore functional abnormalities that may represent state markers in patients with Alzheimer's disease (AD). Methods: Thirteen patients with early AD and 14 age‐matched normal controls participated in the present study. Magnetoencephalography activity was acquired during eyes‐open and eyes‐closed states. Alpha event‐related synchronization (ERS) after eye closing was calculated and its cortical sources superimposed on each individual's magnetic resonance imaging (MRI) scan. The resulting functional image was converted into a Talairach‐transformed anatomical brain image and group comparisons were made. We also assessed correlations between cortical ERS sources showing significant between‐group differences in alpha activity and external clinical parameters, especially measures of cognitive function. Results: The averaged alpha ERS after eye closing appeared dominantly in posterior brain regions in both patients with AD and healthy controls. However, there was a significant increase in alpha ERS in frontal regions, maximal over the prefrontal cortex, in patients with AD relative to controls, indicating a frontal shift of the posterior dominant MEG alpha rhythm in AD patients. This frontal ERS source in the alpha band was negatively correlated with Mini‐Mental State Examination scores in the AD patient group. Conclusions: The findings indicate that a frontal shift of alpha ERS elicited by an eyes‐open/eyes‐closed paradigm may be an early brain electromagnetic change in patients with AD, probably representing a physiological state marker of the disease. Furthermore, the results confirm that the beamformer with group comparison analysis is a useful tool with which to explore functional processes in the brain, as indicated by oscillatory activity changes.     

Spatially filtered magnetoencephalography compared with electrocorticography to identify intrinsically epileptogenic focal cortical dysplasia

This study was carried out to evaluate Synthetic Aperture Magnetometry-kurtosis (SAM(g(2))), a spatially filtered source localization technique in magnetoencephalography (MEG), for identification of epileptogenic areas of focal cortical dysplasia (FCD). Three children with FCD were investigated to localize the ictal onset zone (IOZ). All patients subsequently had extraoperative electrocorticography (ECoG) for intractable epilepsy and surgical resection. SAM(g(2)) analysis showed overlapping of interictal MEG spike sources with the IOZ on ECoG in all children. We recommend MEG-SAM(g(2)) and MEG interictal spike source localization in patients with epileptogenic FCD.     

Efficacy of risperidone in the treatment of delirium in elderly patients

Background:  Despite increasing recognition of delirium as a serious complication of physical illness, little has been reported in this area. Interest has been raised in treatment options other than haloperidol, such as atypical antipsychotic agents.
Methods:  A 2-week open-label trial of risperidone for the treatment of delirium was conducted to assess the efficacy and tolerance of this medication in elderly patients. Twenty-two patients with DSM-IV-defined delirium were investigated. All patients had the hyperactive–hyperalert variant of delirium. Patients received a fixed dose of risperidone (mean 1.5 ± 0.7 mg; range 0.5–3 mg). Delirium was assessed using the Delirium Rating Scale (DRS) at baseline and on Days 1, 3, 5, 7, and 14 after the initiation of risperidone treatment. Clinical and demographic data, as well as risperidone therapy related information, were collected.
Results:  Delirium resolved in all patients over the course of treatment. The mean period over which delirium resolved was 4.0 ± 2.9 days. The mean DRS score at baseline was 20.7 ± 3.0. The DRS score improved from baseline to Day 1 of treatment and continued to improve until the study end-point. Mild side-effects were present in 27.3% of patients. Stepwise logistic regression identified a decrease of 2 points or higher on the DRS on Day 1 associated with side-effects. There were no significant differences in the response to treatment with the different doses of risperidone used.
Conclusion:  Our findings indicate that low-dose risperidone (0.5–3.0 mg/day) is effective and safe for the treatment of delirium in elderly patients, and that an early response on Day 1 of treatment may be associated with side-effects in these patients.