Orientational alignment of amyloidogenic proteins in pre-aggregated solutions.

In the present study we combine dielectric relaxation spectroscopy with generalized Born simulations to explore the role of orientational order for protein aggregation in solutions of bovine pancreatic insulin at various pH conditions. Under aggregation-prone conditions at low pH, insulin monomers prefer antiparallel dipole alignments, which are consistent with the orientation of the monomeric subunits in the dimer structure. This alignment is also true for two dimers, suggesting that already at moderate protein concentrations the species assemble in equilibrium clusters, in which the molecules adopt preferred orientations also found for the protomers of the corresponding oligomers.

Relaxation stretching, fast dynamics, and activation energy: a comparison of molecular and ionic liquids as revealed by depolarized light scattering.

Depolarized light scattering (DLS) spectra of a series of 16 molecular and 6 room temperature ionic liquids are investigated by applying tandem-Fabry-Pérot interferometry, double monochromator, and photon correlation spectroscopy. Temperatures up to well above the melting point, in some cases, even up to the boiling point, are covered, and all liquids can be supercooled. The accessed time constants are between 1 ps and 10 ns; in some cases, even longer times are reached. The susceptibility spectra and likewise the corresponding reorientational correlation functions are characterized by stretching parameter ß(CD) (0.32-0.80) for the long-time decay (α-process), strength of fast dynamics 1 - f, and time scale at shortest times expressed by k(B)T/I* with the apparent quantity I* reflecting essentially inertia effects. An additional (intermediate) power-law regime (or excess wing in the frequency domain) between fast dynamics and the α-process has to be taken into account. For a given system the spectral parameters are virtually temperature independent up to the boiling point, i.e., frequency-temperature superposition applies for the α-process. Among the liquids, the quantity I* correlates with molecular mass, and the larger 1 - f, the smaller the inertial quantity I*. No correlation among 1 - f and ß(CD) is revealed. Testing for correlation of ß(CD) or 1 - f with parameters describing the temperature dependence of the correlation time τ(α), namely, high-temperature activation energy E(∞), fragility m, or glass transition temperature T(g), no significant correlation is found. Regarding molecular vs ionic liquids, no relevant difference in the evolution of their DLS spectra is observed.

Collective rotational dynamics in ionic liquids: a computational and experimental study of 1-butyl-3-methyl-imidazolium tetrafluoroborate.

The aim of this study is the analysis of the rotational motion in ionic liquids, in particular, 1-butyl-3-methyl-imidazolium tetrafluoroborate. By comparing single-particle and collective motion it is found that the Madden-Kivelson relation is fairly fulfilled in long-term simulation studies (>100 ns), i.e., the collective reorientation can be predicted by the corresponding single-particle property and the static dipolar correlation factor, GK. Furthermore, simulated reorientation is in accordance with hydrodynamic theories yielding hydrodynamic radii comparable to van der Waals radii. Since viscosity is the central quantity entering hydrodynamic formulas, we calculated and measured the viscosity of our system in order to have two independent cycles of hydrodynamic evaluation, a computational and an experimental one. While the static dielectric constant agrees with dielectric reflectance experiment, the hydrodynamic radii derived from the experiments are much lower as a consequence of enhanced rotational motion. Even more, a considerable dynamic broadening is observed in the experiments.

Metaphors and models of executive functioning: comment on Giancola (2000).

Clinical researchers have become increasingly interested in considering the role of normal and impaired executive functioning in psychopathology. The concept of executive functions is, however, often used as a metaphor for a wide range of operations that may, on the one hand, be distinct from one another, but also may be integrated in various ways under different information-processing conditions. A clinician's perspective of executive functioning should take full advantage of the rich body of data and theory that has developed in contemporary cognitive neuroscience around functions such as forms of inhibition and controlled (in contrast to automatic) functions, in a variety of cognitive domains such as making decisions and tracking performance.

Age differences in implicit memory: fragmented object identification and category exemplar generation.

In a cross-sectional study of 164 participants aged 21 to 91, the authors examined age differences on two implicit tests, fragmented object identification (FOI) and category exemplar generation (CEG), and on tests of explicit memory, attention, and verbal fluency. FOI results revealed impaired perceptual skill learning in those over 60 and a decrease in perceptual priming across young, middle-aged, and older groups. CEG priming was impaired in those over 80. Regression analysis revealed explicit contamination of priming on both the FOI and CEG tests. Across the three implicit measures, age accounted for 4 to 13% of the variance when explicit memory was controlled. Semantic fluency predicted CEG priming, suggesting possible frontal lobe involvement on the test. Altogether, results indicate that age has a small but reliable influence on implicit memory.

Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations.

Depressed mood increases the relapse risk of abstinent alcoholics; its neurobiological correlates may include reduced serotonin and norepinephrine turnover rates and increased cortisol concentrations during detoxification stress. Neurosteroids such as dehydroepiandrosterone and its sulfate (DHEA and DHEA-S) may antagonize cortisol action and may have mood-elevating effects on their own. We measured severity of depression with Beck's Depression Inventory (BDI) and Hamilton's Depression Rating Scale (HDRS), plasma concentrations of cortisol, DHEA and DHEA-S, and CSF concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and the dopamine metabolite homovanillic acid (HVA) in 21 abstinent alcoholics after 4 weeks of abstinence and in 11 age-matched healthy control subjects. Only CSF MHPG concentrations were reduced in alcoholics compared to control subjects (41.4 +/- 6.6 vs. 53.3 +/- 8.6 pmol/ml). Self-rated depression was significantly correlated with CSF MHPG (Spearman's R = +0.57, P < 0.01), CSF 5-HIAA (R = +0.51, P < 0.05) and plasma cortisol concentrations (R = +0.50, P < 0.05). Negative correlations were found between DHEA-S concentrations and both self-rated depression (R = -0.45, P < 0.05) and observer-rated depression (R = -0.55, P < 0.05). The ratio of DHEA-S to cortisol serum concentrations was also negatively correlated with depression (BDI: R = -0.55, P < 0.01; HDRS: R = -0.63, P < 0.005). Anxiety (Spielberger's State Anxiety Scale) was only associated with CSF MHPG concentrations (R = +0.58, P < 0.01). Our findings point to the importance of noradrenergic dysfunction in the pathogenesis of depression among abstinent alcoholics and indicate that their mood states may also be modulated by a low DHEA-S to cortisol ratio, hypothetically indicative of low stress protection capacities.

Triazolam-induced changes in alcoholic thought processes.

This study was designed to examine and contrast cognitive effects (explicit memory and access to semantic knowledge) of the benzodiazepine Halcion (triazolam) in ten normal volunteers and ten cognitively un-impaired detoxified alcoholics. The two groups were indistinguishable from one another under placebo conditions on all measures of cognitive functioning. Under Halcion test conditions (0.375 mg p.o.), both groups were about equally impaired in their recall of to-be-remembered information. However, alcoholics, were more likely to recall information that they were not asked to remember (intrusion errors) on all measures of explicit remembering. Alcoholics also generated relatively uncommon (low frequency) responses from semantic memory, rather than common, categorically related associations in response to stimuli such as types of vegetables, flowers, and fruit following the administration of Halcion, but were not different from normal volunteers in the types of responses generated under placebo conditions. These findings suggest that a drug challenge that simulates many of the effects of acute alcohol administration induces alcoholics to think and remember differently (qualitatively) from normal volunteers.

Combined nicotinic and muscarinic blockade in elderly normal volunteers: cognitive, behavioral, and physiologic responses.

Establishing a pharmacologic model of the memory deficits of Alzheimer's disease could be an important tool in understanding how memory fails. We examined the combined effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine in eight normal elderly volunteers (age 61.9 +/- 8.3 yrs, SD). Each received four separate drug challenges (scopolamine (0.4 mg i.v.), mecamylamine (0.2 mg/kg up to 15 mg PO), mecamylamine + scopolamine, and placebo). There was a trend toward increased impairment in explicit memory for the mecamylamine + scopolamine condition as compared to scopolamine alone. Increased impairment was also seen for the mecamylamine + scopolamine condition as compared to scopolamine alone in selected behavioral ratings. Pupil size increased when mecamylamine was added to scopolamine, while systolic blood pressure and pulse changed in concordance with ganglionic blockade. These data together with previous brain-imaging results suggest that this muscarinic-nicotinic drug combination may better model Alzheimer's disease than either drug alone.

Dehydroepiandrosterone (DHEA) treatment of depression.

Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA f1p4or DHEA-S levels were openly administered DHEA (30-90 mg/d x 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months: her depression ratings improved 48-72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.

Pharmacologic challenges in Alzheimer disease and normal controls: cognitive modeling in humans.

Alzheimer disease (AD) is a progressive disorder characterized by cognitive and behavioral dysfunction, central to which are deficits in the cholinergic and other neurotransmitter systems. These results in the essential symptoms of dementia, including impairment of memory, judgment, and abstract thinking. The pharmacologic relationships among the various neurotransmitters (e.g., cholinergic, serotonergic, nicotinic, and dopaminergic) are highly complex and are still being investigated. Information on the pharmacologic basis of cognitive and behavioral dysfunction in AD has applications to drug therapy. One method of obtaining this information is by pharmacomodeling, using individual or combined drugs. Joint cholinergic antagonism with both muscarinic and nicotinic blockade combines to produce short-term memory impairment, which approximates to mild AD in normal elderly people. This effect is better than that achieved with either agent alone. Mixed cholinergic and serotonergic antagonism has an effect on the cognitive function of AD patients and on depression-related behavior. Dopaminergic dysfunction is linked with the development of hallucinatory and psychotic symptoms and may also be involved in dysfunction of verbal fluency. Combination pharmacomodeling allows the various behavioral and cognitive deficits in AD to be studied and allows models for drug trials to be developed.

Minimal effects of dextroamphetamine on scopolamine-induced cognitive impairments in humans.

The central anticholinergic drug scopolamine has been used to model aspects of the memory impairment that occurs in Alzheimer's disease and in aging. To determine whether nonspecific stimulant effects can attenuate the cognitive impairment induced by scopolamine, we studied the effects of scopolamine and the stimulant dextroamphetamine in 17 young normal volunteers. After a baseline day of cognitive testing, subjects participated in two study days, in which they received dextroamphetamine (d-AMP) (0.25 mg/kg p.o.) + scopolamine (0.5 mg i.v.) and placebo + scopolamine, in randomized order under double-blind conditions. There were no statistically significant differences in cognitive test performance between the two drug conditions with the exception of one of the category retrieval tasks. Stimulant effects were documented to occur by other measures. We conclude that d-AMP at the dose used does not attenuate the memory impairment induced by scopolamine.

Perspectives on cognitive psychopharmacology research.

This article discusses new perspectives in the psychopharmacology of cognition and analyses the advantages and disadvantages of using drugs as tools to study the mechanisms underlying memory functions. The use of 'stages' in the processing of information as a means for the analysis of cognitive operations is critically discussed as a rigid approach which can only partially accommodate different cognitive functions. Theoretical models of memory 'systems' and allocation of attentional resources are presented alongside findings from the two types of more commonly used drugs in cognitive psychopharmacology: the benzodiazepines (BZ) and the anticholinergics. In a post-hoc analysis of the effects of BZ and scopolamine on memory and attention, it has become clear that these newer theoretical models can accommodate most, but not all, of the effects of BZ and scopolamine on cognition. It is suggested that the development of cognitive tasks on the basis of these models and the execution of prospective studies with drugs as tools taking in to account the 'systems' approach to interpretation of data may be more useful for understanding cognitive functions.

Is cognitive psychopathology plausible? Illustrations from memory research.

OBJECTIVE: To examine the strengths and weaknesses of cognitive psychopathology through the specific examples of the memory impairments associated with the administration of benzodiazepines, with schizophrenia, and with depression. METHOD: These examples are analyzed with reference to a model of memory based on the principle of division between specialized and central processing structures. A basic contention is that it is useful to consider 2 broad classes of processes-automatic, associative, or sensory/perceptual processes on the one hand and intentional, strategic, or reflective processes on the other hand-as being separate. RESULTS: The functional mechanisms of the memory impairments associated with these conditions are beginning to be identified, and there is preliminary evidence that a deficit in an elementary computation may have dramatic consequences on highest cognitive functions. There is also evidence that certain memory impairments are linked to specific dysfunctional outcomes in everyday life. By showing that specific rate-limiting factors of cognitive performance can be identified and are amenable to cognitive interventions, existing data open the door for theoretically and empirically based cognitive remediation of mental disorders. CONCLUSION: The bulk of available evidence (albeit limited) makes the enterprise of cognitive psychopathology quite plausible and convincing.

Monitoring the source of memory in detoxified alcoholics.

The ability to monitor the source of remembered information and related reflective cognitive processes was examined in normal volunteers and detoxified alcoholics. Normal volunteers were very accurate judges of whether remembered events were presented as stimuli or were self-generated, even when memory was tested 2 days later. In contrast, a subgroup of otherwise cognitively unimpaired alcoholics demonstrated impairments in the ability to track the source of remembered knowledge and were also less able to inhibit intrusion errors in recalling information from memory. These findings provide preliminary evidence of an impairment in cognitive control functions in certain alcoholics. This conclusion is supported by associated findings indicating that, among alcoholics, performance on explicit memory tasks that required reflective cognitive operations were positively correlated with glucose utilization rates in left prefrontal, temporal, and posterior orbital frontal cortical regions.

NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers.

A rapidly growing body of preclinical data has implicated the glutamatergic N-methyl-d-aspartate (NMDA) receptor in memory and other cognitive processes. There is comparatively less information about this receptor system in human cognition. We examined the effects of subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, on two forms of memory, free recall and recognition, as well as attention and behavior in a double-blind, placebo-controlled, 1-hour infusion in 15 healthy volunteers. Ketamine produced decrements in free recall, recognition memory, and attention. In addition, ketamine induced a brief psychosis in our healthy volunteers marked by thought disorder and withdrawal-retardation. Ketamine-induced memory impairments were not accounted for by changes in subject's attention and were not significantly related to psychosis ratings. These data suggest that the NMDA receptor plays a direct role in two types of explicit memory. The implications of these data for the pathophysiology of schizophrenia are discussed.

Human pharmacokinetics and tolerability of L-365,260, a novel cholecystokinin-B antagonist.

A study was conducted to examine the tolerability and pharmacokinetics of single and multiple oral doses of L-365,260, a novel antagonist for type B cholecystokinin (CCK) receptors and to quantify effects of selective blockade of type B CCK receptors through treatment with L-365,260 on measures of anxiety, hunger, and cognitive performance. Healthy volunteers were given single oral doses of up to 50 mg of L-365,260 and multiple oral doses of up to 25 mg every 6 hours for 10 days. Plasma concentrations of L-365,260 were quantified by means of high-performance liquid chromatography. Anxiety and hunger were assessed by visual analog scale and the Spielberger State Anxiety Index. Cognitive testing was used to evaluate attention level and short-term memory. L-365,260 was rapidly absorbed and a biphasic pattern of elimination was demonstrated with a terminal half-life (t1/2) of 8 to 12 hours. The mean (n = 6) values for peak plasma concentration (C(max)) and time to peak concentration (t(max)) of L-365,260 were 503 ng/mL and 1.25 hours, respectively, after a single 50-mg oral dose. Accumulation of L-365,260 plasma concentrations was seen after the prescribed multiple-dose regimens. Steady state was achieved after 3 days of oral administration. L-365,260 had an acceptable tolerability profile after oral administration. No changes in measures of anxiety, hunger, or short-term memory were observed at doses of L-365,260 shown to have antagonist activity at the CCK-B receptor.

Encoding, remembering and awareness in lorazepam-induced amnesia.

The effects of lorazepam (1,2 mg) and placebo on encoding, remembering and awareness were assessed in a study with 54 healthy volunteers. All subjects studied stimulus materials in a levels of processing (L-o-p) task. Half the subjects were assessed on an explicit memory task of word recognition and the other half were given an implicit memory task of word-stem completion. Following the implicit task, awareness of retrieval was further investigated by questions and by subjects' recollective experience in recognising the actual words they had completed from stems. L-o-p effects and marked lorazepam-induced impairments were found in the implicit task of word-stem completion although the interaction between L-o-p and drug effects emerged only as a trend in the data. Lorazepam-induced impairments on stem-completion may then be explained at least in part as being due to contamination by explicit retrieval processes, but we cannot rule out the possible role of drug effects on perceptual processes at encoding. Results from responses to "awareness" questions and from analysis of subsequent recollective experience indicated that subjects were not aware of using explicit retrieval during the implicit task. Results also replicated previous findings showing that both lorazepam and L-o-p independently affect performance in an explicit memory task of word recognition. Thus drug-induced deficits at encoding persist regardless of the level at which information is initially processed.

An effect of triazolam on visual attention and information processing.

This study explored whether benzodiazepines selectively affect aspects of attention and/or visual information processing, as they do memory. A cued visual-search paradigm was employed, using normal volunteers and a single dose of triazolam. This paradigm provided for a detailed examination of two aspects of visual attention and information processing: 1) controlled versus automatic attention allocation (via central and peripheral cues), and 2) the extent to which processing an item in a non-cued location affects performance (via cue-validity). Triazolam, compared to placebo, significantly increased response time, and Drug Condition interacted with Cue-Validity but not Cue-Type. Based on these data, we argue that triazolam does not affect attention allocation but does affect attentional disengagement and/or attention switching mechanisms.