Modulation of Amyloid-ß and Tau in Alzheimer's Disease Plasma Neuronal-Derived Extracellular Vesicles by Cerebrolysin® and Donepezil.

BACKGROUND: Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. OBJECTIVE: We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD. METHODS: Plasma NDEV levels of Aß42, total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. RESULTS: NDEV levels of Aß42, total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV Aß42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-α (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV Aß42 with respect to monotherapies (p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05). CONCLUSION: The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs.

Study of Room Temperature Ionic Liquids as Gas Sensing Materials in Quartz Crystal Microbalances.

Twenty-eight quartz crystal microbalance (QCM) sensors coated with different sensing films were tested and analyzed in this work; twenty-three sensors were coated in different room temperature ionic liquids (RTILs) and five additional QCM sensors were coated with conventional films commonly used as stationary phases in gas chromatography. Four volatile organic compounds (VOCs), in gaseous phase-hexanol, butyl acetate, 2-hexanone, and hexanoic acid-were measured. Two transducer mechanisms were used; resonant frequency shift and resistance shift of a QCM Mason equivalent circuit. The sensors were characterized by their sensitivity to the VOCs and their discrimination power of the four VOCs. The highest separation among VOCs was obtained when frequency and resistance information of both RTIL and conventional films was used, a sensor array composed by two RTILs (1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide and 1-hexyl-3-methylimidazolium hexafluorophosphate) and two conventional films (tricresyl phosphate and apiezon-L) was found to improve the Wilks lambda separation for the tested gases two orders of magnitude compared to the Wilks lambda using only a conventional films array.

Serum VEGF Predicts Clinical Improvement Induced by Cerebrolysin Plus Donepezil in Patients With Advanced Alzheimer's Disease.

Serum vascular endothelial growth factor (VEGF) increases with Alzheimer's disease (AD) severity and may prevent cognitive decline. However, information on the influence of AD drug therapy on circulating VEGF is limited. This study assessed changes in serum VEGF levels and its association with clinical and functional responses in mild to moderate AD patients who were treated with Cerebrolysin, donepezil, or the combined therapy in a randomized, controlled trial. Treatment with Cerebrolysin plus donepezil reduced elevated serum VEGF levels and improved functioning and cognition significantly compared with donepezil alone in patients with advanced AD, and treatment differences were more pronounced in patients with higher VEGF levels. Our results indicate that the combined therapy reversed the increase of serum VEGF in advanced AD, which was associated with cognitive and functional responses, particularly in patients with high baseline VEGF.

Optimization of Modulation Methods for Solenoid Valves to Realize an Odor Generation System.

An artificial olfactory system coupled with an odor generation system is herein reported. The artificial olfactory system is composed of four chemical sensors consisting of quartz crystal microbalances (QCMs) coated with room temperature ionic liquids (RTILs). The sensors are interrogated by four vector network analyzers, which are used to measure the series resonant frequency and motional resistance. The odor generation system can generate eight different odors and mix them in any composition. Solenoid valves are used to switch the path and control the concentration of the different odors before blending. Two algorithms to control the solenoid valves, delta-sigma modulator, and simple pulse width modulation (PWM) are studied, optimized, and compared. Finally, the uncertainty of the odor generating system is calculated.

Development of Tin Oxide-Based Nanosensors for Electronic Nose Environmental Applications.

Tin oxide nanofibres (NFs) are used as nanosensors in electronic noses. Their performance is compared to that of oxide commercial chemical sensors for pollutant detection. NFs were grown by electrospinning and deposited onto silicon substrates with integrated micro-hotplates. NF morphology was characterized by scanning electron microscopy (SEM). The NFs presented high sensitivity to NO2 at low temperature.

Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers.

Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

Quantification of Wine Mixtures with an Electronic Nose and a Human Panel.

In this work, an electronic nose and a human panel were used for the quantification of wines formed by binary mixtures of four white grape varieties and two varieties of red wines at different percentages (from 0 to 100% in 10% steps for the electronic nose and from 0 to 100% in 25% steps for the human panel). The wines were prepared using the traditional method with commercial yeasts. Both techniques were able to quantify the mixtures tested, but it is important to note that the technology of the electronic nose is faster, simpler, and more objective than the human panel. In addition, better results of quantification were also obtained using the electronic nose.

Longitudinal estimation of intramuscular Tibialis Anterior coherence during subacute spinal cord injury: relationship with neurophysiological, functional and clinical outcome measures.

BACKGROUND: Estimation of surface intramuscular coherence has been used to indirectly assess pyramidal tract activity following spinal cord injury (SCI), especially within the 15-30 Hz bandwidth. However, change in higher frequency (>40 Hz) muscle coherence during SCI has not been characterised. Thus, the objective of this study was to identify change of high and low frequency intramuscular Tibialis Anterior (TA) coherence during incomplete subacute SCI. METHODS: Fifteen healthy subjects and 22 subjects with motor incomplete SCI (American Spinal Injury Association Impairment Scale, AIS, C or D grade) were recruited and tested during 4 sessions performed at 2-week intervals up to 8 months after SCI. Intramuscular TA coherence estimation was calculated within the 10-60 Hz bandwidth during controlled maximal isometric and isokinetic foot dorsiflexion. Maximal voluntary dorsiflexion torque, gait function measured with the WISCI II scale, and TA motor evoked potentials (MEP) were recorded. RESULTS: During subacute SCI, significant improvement in total lower limb manual muscle score, TA muscle strength and gait function were observed. No change in TA MEP amplitude was identified. Significant increase in TA coherence was detected in the 40-60 Hz, but not the 15-30 Hz bandwidth. The spasticity syndrome was associated with lower 15-30 Hz TA coherence during maximal isometric dorsiflexion and higher 10-60 Hz coherence during fast isokinetic movement (p < 0.05). CONCLUSIONS: Longitudinal estimation of neurophysiological and clinical measures during subacute SCI suggest that estimation of TA muscle coherence during controlled movement provides indirect information regarding adaptive and maladaptive motor control mechanisms during neurorehabilitation.

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases.

BACKGROUND: Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer's disease. METHODS: We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer's disease patients. RESULTS: Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy. CONCLUSION: Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer's disease cases with apolipoprotein E epsilon-4 allele.

A wireless and portable electronic nose to differentiate musts of different ripeness degree and grape varieties.

Two novel applications using a portable and wireless sensor system (e-nose) for the wine producing industry-The recognition and classification of musts coming from different grape ripening times and from different grape varieties-Are reported in this paper. These applications are very interesting because a lot of varieties of grapes produce musts with low and similar aromatic intensities so they are very difficult to distinguish using a sensory panel. Therefore the system could be used to monitor the ripening evolution of the different types of grapes and to assess some useful characteristics, such as the identification of the grape variety origin and to prediction of the wine quality. Ripening grade of collected samples have been also evaluated by classical analytical techniques, measuring physicochemical parameters, such as, pH, Brix, Total Acidity (TA) and Probable Grade Alcoholic (PGA). The measurements were carried out for two different harvests, using different red (Barbera, Petit Verdot, Tempranillo, and Touriga) and white (Malvar, Malvasía, Chenin Blanc, and Sauvignon Blanc) grape musts coming from the experimental cellar of the IMIDRA at Madrid. Principal Component Analysis (PCA) and Probabilistic Neural Networks (PNN) have been used to analyse the obtained data by e-nose. In addition, and the Canonical Correlation Analysis (CCA) method has been carried out to correlate the results obtained by both technologies.

Apathy and APOE4 are associated with reduced BDNF levels in Alzheimer's disease.

Reduced brain-derived neurotrophic factor (BDNF) signaling is considered as a pathogenic event in early Alzheimer's disease (AD), but the influence of apathy and apolipoprotein E ε4 allele (APOE4) on serum BDNF values was not previously investigated in AD. We evaluated serum BDNF levels in AD, amnestic mild cognitive impairment (MCI), and control subjects. Baseline BDNF levels were similar in AD, MCI, and controls. AD patients having apathy showed lower BDNF values than patients without apathy (p < 0.05). After correction for the influence of apathy, APOE4 carriers showed lower BDNF levels (p < 0.01) and MMSE scores (p < 0.01) than non-APOE4 carriers in the subgroup of AD females, but not in males. Significant (p < 0.05) positive correlations between BDNF values and MMSE scores were only observed in subgroups of AD males and of AD patients without apathy. These results are showing the association of apathy and APOE4 with reduced serum BDNF levels in AD, and are suggesting that BDNF reductions might contribute to the worse cognitive performance exhibited by AD apathetic patients and female APOE4 carriers.

Tibialis Anterior muscle coherence during controlled voluntary activation in patients with spinal cord injury: diagnostic potential for muscle strength, gait and spasticity.

BACKGROUND: Coherence estimation has been used as an indirect measure of voluntary neurocontrol of residual motor activity following spinal cord injury (SCI). Here intramuscular Tibialis Anterior (TA) coherence estimation was performed within specific frequency bands for the 10-60 Hz bandwidth during controlled ankle dorsiflexion in subjects with incomplete SCI with and without spasticity. METHODS: In the first cohort study 15 non-injured and 14 motor incomplete SCI subjects were recruited to evaluate TA coherence during controlled movement. Specifically 15-30 Hz EMG was recorded during dorsiflexion with: i) isometric activation at 50, 75 and 100% of maximal voluntary torque (MVT), ii) isokinetic activation at 60 and 120°/s and iii) isotonic dorsiflexion at 50% MVT. Following identification of the motor tasks necessary for measurement of optimal TA coherence a second cohort was analyzed within the 10-16 Hz, 15-30 Hz, 24-40 Hz and 40-60 Hz bandwidths from 22 incomplete SCI subjects, with and without spasticity. RESULTS: Intramuscular 40-60 Hz, but not 15-30 Hz TA, coherence calculated in SCI subjects during isometric activation at 100% of MVT was lower than the control group. In contrast only isometric activation at 100% of MVT 15-30 Hz TA coherence was higher in subjects with less severe SCI (AIS D vs. AIS C), and correlated functionally with dorsiflexion MVT. Higher TA coherence was observed for the SCI group during 120°/s isokinetic movement. In addition 15-30 Hz TA coherence calculated during isometric activation at 100% MVT or 120°/s isokinetic movement correlated moderately with walking function and time from SCI, respectively. Spasticity symptoms correlated negatively with coherence during isometric activation at 100% of MVT in all tested frequency bands, except for 15-30 Hz. Specifically, 10-16 Hz coherence correlated inversely with passive resistive torque to ankle dorsiflexion, while clinical measures of muscle hypertonia and spasm severity correlated inversely with 40-60 Hz. CONCLUSION: Analysis of intramuscular 15-30 Hz TA coherence during isometric activation at 100% of MVT is related to muscle strength and gait function following incomplete SCI. In contrast several spasticity symptoms correlated negatively with 10-16 Hz and 40-60 Hz TA coherence during isometric activation at 100% MVT. Validation of the diagnostic potential of TA coherence estimation as a reliable and comprehensive measure of muscle strength, gait and spasticity should facilitate SCI neurorehabilation.

Threshold detection of aromatic compounds in wine with an electronic nose and a human sensory panel.

An electronic nose (e-nose) based on thin film semiconductor sensors has been developed in order to compare the performance in threshold detection and concentration quantification with a trained human sensory panel in order to demonstrate the use of an e-nose to assess the enologists in an early detection of some chemical compounds in order to prevent wine defects. The panel had 25 members and was trained to detect concentration thresholds of some compounds of interest present in wine. Typical red wine compounds such as whiskeylactone and white wine compounds such as 3-methyl butanol were measured at different concentrations starting from the detection threshold found in literature (in the nanograms to milligrams per liter range). Pattern recognition methods (principal component analysis (PCA) and neural networks) were used to process the data. The results showed that the performance of the e-nose for threshold detection was much better than the human panel. The compounds were detected by the e-nose at concentrations up to 10 times lower than the panel. Moreover the e-nose was able to identify correctly each concentration level therefore quantitative applications are devised for this system.

Reduced TNF-α and increased IGF-I levels in the serum of Alzheimer's disease patients treated with the neurotrophic agent cerebrolysin.

According to current scientific knowledge, excess tumour necrosis factor-α (TNF-α) and low insulin-like growth factor-I (IGF-I) are pathogenic-risk factors that constitute therapeutic targets for Alzheimer's disease (AD). Changes in serum TNF-α, total and dissociable IGF-I levels were determined by ELISA in 207 AD patients completing a 24-wk, double-blind, placebo-controlled trial to evaluate the effects of the neurotrophic compound Cerebrolysin (Cere: 10, 30 or 60 ml for 12 wk). At week 24, Cere reduced TNF-α and enhanced dissociable IGF-I with respect to placebo in a dose-related manner. TNF-α decreased in parallel with behavioural disturbances. Increases in total IGF-I were induced by 60 ml Cere and correlated significantly with improvements in global function, disabilities and behaviour in late-onset AD patients. These results showing for the first time the opposite influence of one anti-dementia treatment on serum TNF-α and IGF-I suggest the contribution of both factors to the clinical effects of Cere, and probably other drugs.

Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease.

Tumor necrosis factor-alpha (TNF-alpha) and insulin-like growth factor-I (IGF-I) have been involved in the pathogenesis of Alzheimer's disease (AD) as neurotoxic and survival factors, respectively. Recent experimental studies suggest that the signalling pathways of TNF-alpha and IGF-I are functionally interrelated. In order to investigate the possible interaction of TNF-alpha and IGF-I in AD and mild cognitive impairment (MCI), the serum levels of total IGF-I, free IGF-I and TNF-alpha were determined in 141 AD patients, 56 MCI cases and 30 controls. As compared with controls, AD patients showed increased TNF-alpha and decreased IGF-I levels in serum, as well as a significant negative correlation between TNF-alpha and free IGF-I values. MCI patients also exhibited significantly higher TNF-alpha levels than controls. The present results suggest that increased TNF-alpha levels are involved in the pathogenesis of AD and MCI, and might antagonize the neurotrophic activity of IGF-I in these medical conditions. In addition, the combined determination of TNF-alpha and IGF-I might be useful to monitor anti-inflammatory and/or neurotrophic drug effects in AD.

Positive effects of cerebrolysin on electroencephalogram slowing, cognition and clinical outcome in patients with postacute traumatic brain injury: an exploratory study.

The potential effects of Cerebrolysin (EBEWE Pharma, Unterach, Austria), a peptide preparation with neurotrophic activity, on brain bioelectrical activity, cognitive performance and clinical outcome in postacute traumatic brain injury (TBI) patients, were investigated in an exploratory study. A decrease in slow electroencephalogram (EEG) activity and an increase in fast frequencies were observed after the administration of Cerebrolysin. This EEG-activating effect was not influenced by TBI time course or severity, nor by the chronic treatment with nootropic compounds. Cognitive performance, evaluated with the Syndrome Kurztest test, improved in TBI patients after Cerebrolysin treatment, independent of disease severity, time course or disability. A significant improvement in the patients' clinical outcome, only evident during the first year after brain trauma, was also found following Cerebrolysin infusions. No relevant changes in biological parameters nor drug-related adverse events were observed. These promising preliminary results suggest that Cerebrolysin might be a useful treatment to improve the recovery of patients with traumatic brain damage, and encourage the conduction of confirmatory clinical trials.

Detection of Iberian ham aroma by a semiconductor multisensorial system.

A semiconductor multisensorial system, based on tin oxide, to control the quality of dry-cured Iberian hams is described. Two types of ham (submitted to different drying temperatures) were selected. Good responses were obtained from the 12 elements forming the multisensor for different operating temperatures. Discrimination between the two types of ham was successfully realised through principal component analysis (PCA).