GABA and glutamate moderate beta-amyloid related functional connectivity in cognitively unimpaired old-aged adults.

BACKGROUND: Effects of beta-amyloid accumulation on neuronal function precede the clinical manifestation of Alzheimer's disease (AD) by years and affect distinct cognitive brain networks. As previous studies suggest a link between beta-amyloid and dysregulation of excitatory and inhibitory neurotransmitters, we aimed to investigate the impact of GABA and glutamate on beta-amyloid related functional connectivity. METHODS: 29 cognitively unimpaired old-aged adults (age = 70.03 ±â€¯5.77 years) were administered 11C-Pittsburgh Compound B (PiB) positron-emission tomography (PET), and MRI at 7 Tesla (7T) including blood oxygen level dependent (BOLD) functional MRI (fMRI) at rest for measuring static and dynamic functional connectivity. An advanced 7T MR spectroscopic imaging (MRSI) sequence based on the free induction decay acquisition localized by outer volume suppression' (FIDLOVS) technology was used for gray matter specific measures of GABA and glutamate in the posterior cingulate and precuneus (PCP) region. RESULTS: GABA and glutamate MR-spectra indicated significantly higher levels in gray matter than in white matter. A global effect of beta-amyloid on functional connectivity in the frontal, occipital and inferior temporal lobes was observable. Interactive effects of beta-amyloid with gray matter GABA displayed positive PCP connectivity to the frontomedial regions, and the interaction of beta-amyloid with gray matter glutamate indicated positive PCP connectivity to frontal and cerebellar regions. Furthermore, decreased whole-brain but increased fronto-occipital and temporo-parietal dynamic connectivity was found, when GABA interacted with regional beta-amyloid deposits in the amygdala, frontal lobe, hippocampus, insula and striatum. CONCLUSIONS: GABA, and less so glutamate, may moderate beta-amyloid related functional connectivity. Additional research is needed to better characterize their interaction and potential impact on AD.

Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment.

Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aß) plaque-load in a context of increased risk for Alzheimer's disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aß-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aß-plaque-load was observable both for cortical and subcortical brain-regions. APOE-e4 and MCI was also associated with higher cortical iron. Moreover, cerebral iron significantly affected functional coupling, and was furthermore associated with increased Aß-plaque-load (R2-adjusted = 0.80, p < 0.001) and APOE-e4 carrier status (p < 0.001) in MCI. This study confirms earlier reports on an association between increased brain iron-burden and risk for neurocognitive dysfunction due to AD, and indicates that disease-progression is conferred by spatial colocalization of brain iron deposits with Aß-plaques.

Can actions affect perceptual processing?

Previous studies reported impairments in a perceptual task performed during the selection and execution of an action. These findings, however, always raise the question of whether the impairment actually reflects a reduction in perceptual sensitivity or whether it results only from an unspecific reduction in attentiveness given the perceptual task. Recent studies by the authors indicate that actions can also have a specific impact on perception in a dual-task situation. The identification of a left or right arrow is impaired when it appears during the execution of a compatible left or right keypress. In three experiments Signal Detection Theory is applied to test whether this impairment is also found in the sensitivity measure d' or whether it originates only from a response tendency. The results revealed a general lower d' for the identification of arrows that were compatible to simultaneously executed keypresses than for arrows that were incompatible. The bias measure c was small and/or did not differ between conditions. Additional analyses revealed that the impairment is due to a higher mean perceptual degradation of stimuli in the compatible condition and that it is restricted to the point in time when the central movement command is generated. Thus, actions actually seem able to affect perceptual processing.

Synthesis and characterisation of mucoadhesive thiolated polymers.

This study examined various factors influencing the mucoadhesive properties of thiolated polymers (thiomers), which are capable of forming covalent bonds with thiol sub-structures of the mucus glycoprotein. Mediated by a carbodiimide, L-cysteine was therefore covalently bound to polycarbophil (PCP) and to carboxymethylcellulose (CMC). The resulting polymer conjugates displayed 12.3 and 22.3 micromol thiol groups per gram, respectively. Whereas the swelling behaviour of tablets based on CMC was not markedly influenced by the immobilisation of cysteine, it was improved significantly (P<0.05) in case of PCP. Tensile studies carried out with the unmodified and thiolated polymers of pH 3, 5 and 7, respectively, revealed that only if the polymer displays a pH-value of 5, the total work of adhesion can be improved significantly due to the covalent attachment of thiol groups. These results were in good agreement with a new mucoadhesion test system described here taking also the cohesiveness of the delivery system into account. The results represent helpful basic information in order to improve the mucoadhesive properties of thiolated polymers.

Polymers with thiol groups: a new generation of mucoadhesive polymers?

PURPOSE: To improve the mucoadhesive properties of polycarbophil by the introduction of sulfhydryl groups. METHODS: Mediated by a carbodiimide, cysteine was covalently bound to polycarbophil (PCP) forming amide bonds between the primary amino group of the amino acid and the carboxylic acid moieties of the polymer. The amount of covalently attached cysteine and the formation of disulfide bonds within the modified polymer were determined by quantifying the share of thiol groups on the polymer conjugates with Ellman's reagent. The adhesive properties of polycarbophil-cysteine conjugates were evaluated in vitro on excised porcine intestinal mucosa by determining the total work of adhesion (TWA). RESULTS: Depending on the weight-ratio of polycarbophil to cysteine at the coupling reaction, e.g., 16:1 and 2:1, 0.6+/-0.7 micromole and 5.3+/-2.4 micromole cysteine, respectively, were covalently bound per g polymer. The modified polymer displayed improved internal cohesive properties due to the formation of interchain disulfide bonds within the polymer in aqueous solutions at pH-values above 5. Adhesion studies revealed strongly improved adhesive properties. Whereas the TWA was determined to be 104+/-21 microJ for the unmodified polymer, it was 191+/-47 microJ for the polymer-cysteine conjugate 16:1 and 280+/-67 microJ for the polymer-cysteine conjugate 2:1. CONCLUSIONS: Polymers with thiol groups might represent a new generation of mucoadhesive polymers displaying comparatively stronger adhesive properties.