Hypothesis: is Alzheimer's disease a metal-induced immune disorder?

A hypothesis that a metal-induced immune disorder may be involved in the pathogenesis of some forms of Alzheimer's disease (AD) is presented. The classical complement pathway is activated in AD and T cells and reactive microglia appear in the brain. Studies of metal induced autoimmunity and the use of compounds containing aluminium as vaccine adjuvants suggest that metals can activate complement and can be taken up by antigen presenting cells. The consequent immune response could contribute to neuronal damage, beta-amyloid deposition and cell death. The strengths and weaknesses of this hypothesis are discussed and tests of some aspects are proposed.

A demonstration of attentional bias, using a novel dual task paradigm, towards clinically salient material in recovering alcohol abuse patients?

Background. This study examined whether alcohol abuse patients are characterized either by enhanced schematic processing of alcohol related cues or by an attentional bias towards the processing of alcohol cues. Method. Abstinent alcohol abusers (N = 25) and non-clinical control participants (N = 24) performed a dual task paradigm in which they had to make an odd/even decision to a centrally presented number while performing a peripherally presented lexical decision task. Stimuli on the lexical decision task comprised alcohol words, neutral words and non-words. In addition, participants completed an incidental recall task for the words presented in the lexical decision task. Results. It was found that, in the presence of alcohol related words, the performance of patients on the odd/even decision task was poorer than in the presence of other stimului. In addition, patients displayed slower lexical decision times for alcohol related words. Both groups displayed better recall for alcohol words than for other stimuli. Conclusions. These results are interpreted as supporting neither model of drug cravings. Rather, it is proposed that, in the presence of alcohol stimuli, alcohol abuse patients display a breakdown in the ability to focus attention.

Techniques for determining bias and stability in satellite altimeters

The case for monitoring large-scale sea level variability is established in the context of the estimation of the extent of anthropogenic climate change. Satellite altimeters are identified as having the potential to monitor this change with high resolution and accuracy. Possible sources of systematic errors and instabilities in these instruments which would be hurdles to the most accurate monitoring of such ocean signals are examined. Techniques for employing tide gauges to combat such inaccuracies are proposed and developed. The tide gauge at Newhaven in Sussex is used in conjunction with the nearby satellite laser ranger and high-resolution ocean models to estimate the absolute bias of the TOPEX, Poseidon, ERS 1 and ERS 2 altimeters. The theory which underlies the augmentation of altimeter measurements with tide gauge data is developed. In order to apply this, the tide gauges of the World Ocean Circulation Experiment are assessed and their suitability for altimeter calibration is determined. A reliable subset of these gauges is derived. A method of intra-altimeter calibration is developed using these tide gauges to remove the effect of variability over long time scales. In this way the long-term instability in the TOPEX range measurement is inferred and the drift arising from the on-board ultra stable oscillator is thus detected. An extension to this work develops a method for inter-altimeter calibration, allowing the systematic differences between unconnected altimeters to be measured. This is applied to the TOPEX and ERS 1 altimeters.

The pathogenesis of Alzheimer's disease: a reevaluation of the "amyloid cascade hypothesis"

The most influential theory to explain the pathogenesis of Alzheimer's disease (AD) has been the "Amyloid Cascade Hypothesis" (ACH) first formulated in 1992. The ACH proposes that the deposition of ß-amyloid (Aß) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

Self-assembly of trehalose molecules on a lysozyme surface: the broken glass hypothesis

To help understand how sugar interactions with proteins stabilise biomolecular structures, we compare the three main hypotheses for the phenomenon with the results of long molecular dynamics simulations on lysozyme in aqueous trehalose solution (0.75 M). We show that the water replacement and water entrapment hypotheses need not be mutually exclusive, because the trehalose molecules assemble in distinctive clusters on the surface of the protein. The flexibility of the protein backbone is reduced under the sugar patches supporting earlier findings that link reduced flexibility of the protein with its higher stability. The results explain the apparent contradiction between different experimental and theoretical results for trehalose effects on proteins.

The effects of negative affectivity on self-reported activity limitations in stroke patients:testing the symptom perception, disability and psychosomatic hypotheses

This study investigated whether Negative Affectivity (NA) causes bias in self-report measures of activity limitations or whether NA has a real, non-artifactual association with activity limitations. The Symptom Perception Hypothesis (NA negatively biases self-reporting), Disability Hypothesis (activity limitations cause NA) and Psychosomatic Hypothesis (NA causes activity limitations) were examined longitudinally using both self-report and objective activity limitations measures. Participants were 101 stroke patients and their caregivers interviewed within two weeks of discharge, six weeks later and six months post-discharge. NA and self-report, proxy-report and observed performance activity (walking) limitations were assessed at each interview. NA was associated with activity limitations across measures. Both the Disability and Psychosomatic Hypotheses were supported: initial NA predicted objective activity limitations at six weeks but, additionally, activity limitations at six weeks predicted NA at six months. These results suggest that NA both affects and is affected by activity limitations and does not simply influence reporting.

Further studies on the patterns of senile plaques in senile dementia of the Alzheimer type (SDAT) with a hypothesis on the colonization of the cortex

The pattern of senile plaques was investigated in various brain regions of six SDAT brains. In 91 pattern analyses, the regularly spaced clump was the most common pattern found in 64.8% of analyses. Clumping due to large aggregations of uncored plaques in sulci was also common. Regularly spaced clumps were equally common in the hippocampus and neocortex. The pattern of plaques varied in different tissue sections from the same brain region. Cored and uncored plaques presented a similar range of patterns but their pattern varied when they were both present in the same tissue section. Both clump diameter and the intensity of clumping were positively correlated with cored but unrelated to uncored plaque density. Plaques may develop in regular clumps on subcortical afferents and during development of the disease the clumps may spread laterally and ultimately coalesce.

The spatial patterns of plaques and tangles in Alzheimer's disease do not support the 'cascade hypothesis'

In Alzheimer's disease (AD), the 'Cascade hypothesis' proposes that the formation of paired helical filaments (PHF) may be casually linked to the deposition of beta/A4 protein. Hence, there should be a close spatial relationship between senile plaques and cellular neurofibrillary tangles in a local region of the brain. In tissue from 6 AD patients, plaques and tangles occurred in clusters and individual clusters were often regularly spaced along the cortical strip. However, the clusters of plaques and tangles were in phase in only 4/32 cortical tissues examined. Hence, the data were not consistent with the 'Cascade hypothesis' that beta/A4 and PHF are directly linked in AD.

Memory bias for emotional facial expressions in major depression

Sixteen clinically depressed patients and sixteen healthy controls were presented with a set of emotional facial expressions and were asked to identify the emotion portrayed by each face. They, were subsequently given a recognition memory test for these faces. There was no difference between the groups in terms of their ability to identify emotion between from faces. All participants identified emotional expressions more accurately than neutral expressions, with happy expressions being identified most accurately. During the recognition memory phase the depressed patients demonstrated superior memory for sad expressions, and inferior memory for happy expressions, relative to neutral expressions. Conversely, the controls demonstrated superior memory for happy expressions, and inferior memory for sad expressions, relative to neutral expressions. These results are discussed in terms of the cognitive model of depression proposed by Williams, Watts, MacLeod, and Mathews (1997).

A working memory bias for alcohol-related stimuli depends on drinking score

We tested 44 participants with respect to their working memory (WM) performance on alcohol-related versus neutral visual stimuli. Previously an alcohol attentional bias (AAB) had been reported using these stimuli, where the attention of frequent drinkers was automatically drawn toward alcohol-related items (e.g., beer bottle). The present study set out to provide evidence for an alcohol memory bias (AMB) that would persist over longer time-scales than the AAB. The WM task we used required memorizing 4 stimuli in their correct locations and a visual interference task was administered during a 4-sec delay interval. A subsequent probe required participants to indicate whether a stimulus was shown in the correct or incorrect location. For each participant we calculated a drinking score based on 3 items derived from the Alcohol Use Questionnaire, and we observed that higher scorers better remembered alcohol-related images compared with lower scorers, particularly when these were presented in their correct locations upon recall. This provides first evidence for an AMB. It is important to highlight that this effect persisted over a 4-sec delay period including a visual interference task that erased iconic memories and diverted attention away from the encoded items, thus the AMB cannot be reduced to the previously reported AAB. Our finding calls for further investigation of alcohol-related cognitive biases in WM, and we propose a preliminary model that may guide future research. © 2012 American Psychological Association.

Genetic modulation of the response bias towards facial displays of anger and happiness

Background: Investigating genetic modulation of emotion processing may contribute to the understanding of heritable mechanisms of emotional disorders. The aim of the present study was to test the effects of catechol- O-methyltransferase (COMT) val158met and serotonin-transporter-linked promoter region (5-HTTLPR) polymorphisms on facial emotion processing in healthy individuals. Methods: Two hundred and seventy five (167 female) participants were asked to complete a computerized facial affect recognition task, which involved four experimental conditions, each containing one type of emotional face (fearful, angry, sad or happy) intermixed with neutral faces. Participants were asked to indicate whether the face displayed an emotion or was neutral. The COMT-val158met and 5-HTTLPR polymorphisms were genotyped. Results: Met homozygotes (COMT) showed a stronger bias to perceive neutral faces as expressions of anger, compared with val homozygotes. However, the S-homozygotes (5-HTTLPR) showed a reduced bias to perceive neutral faces as expressions of happiness, compared to L-homozygotes. No interaction between 5-HTTLPR and COMT was found. Conclusions: These results add to the knowledge of individual differences in social cognition that are modulated via serotonergic and dopaminergic systems. This potentially could contribute to the understanding of the mechanisms of susceptibility to emotional disorders. © 2013 Elsevier Masson SAS.