A European Academy of Neurology guideline on medical management issues in dementia.

BACKGROUND AND PURPOSE: Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow-up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia. METHODS: A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated. RESULTS: Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk-benefit ratio should be performed at regular intervals. Regular, preplanned medical follow-up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non-pharmacological measures have been proven to be without benefit or in the case of severe self-harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first-line therapy (Good Practice statement). CONCLUSION: This GRADE-based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas.

Hospital admissions and emergency department visits for people with dementia.

BACKGROUND: Previous studies have suggested that people with dementia (PwD) are more likely to be admitted to hospital, have prolonged hospital stay, or visit an emergency department (ED), compared to people without dementia. AIM: This study assessed the rates of hospital admissions and ED visits in PwD and investigated the causes and factors predicting this healthcare use. Further, this study assessed survival following hospital admissions and ED visits. DESIGN: This was a retrospective study with data from 26 875 PwD and 23 961 controls. METHODS: Data from national datasets were extracted for demographic characteristics, transitions to care homes, hospital and ED use and were linked through the Honest Broker Service. PwD were identified through dementia medication and through causes for hospital admissions and death. RESULTS: Dementia was associated with increased risk of hospital admissions and ED visits, and with lower odds of hospital readmission. Significant predictors for hospital admissions and readmissions in PwD were transitioning to a care home, living in urban areas and being widowed, while female gender and living in less deprived areas reduced the odds of admissions. Older age and living in less deprived areas were associated with lower odds of an ED visit for PwD. In contrast to predictions, mortality rates were lower for PwD following a hospital admission or ED visit. CONCLUSIONS: These findings result in a better understanding of hospital and ED use for PwD. Surprisingly, survival for PwD was prolonged following hospital admissions and ED visits and thus, policies and services enabling these visits are necessary, especially for people who live alone or in rural areas; however, increased primary care and other methods, such as eHealth, could provide equally effective care in order to avoid distress and costs for hospital admissions and ED visits.

Genome-wide association study of Alzheimer's disease with psychotic symptoms.

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.

Retinal drusen: harbingers of age, safe havens for trouble.

Drusen are small focal extracellular deposits underneath the retina, visible ophthalmoscopically as yellow dots. The more hard drusen there are, the greater the risk of developing soft drusen and retinal pigmentary changes, which in turn increase the risk of developing advanced age-related macular degeneration. Much remains to be discovered about drusen. For the patient with drusen, basic advice on diet and smoking and maintenance of a high level of vigilance for visual changes is appropriate management.

The effects of blood pressure lowering on development of cognitive impairment and dementia in patients without apparent prior cerebrovascular disease.

BACKGROUND: Hypertension and cognitive impairment are prevalent in older people. It is known that hypertension is a direct risk factor for vascular dementia and recent studies have suggested hypertension also impacts upon prevalence of Alzheimer's disease. The question is therefore whether treatment of hypertension lowers the rate of cognitive decline. OBJECTIVES: To assess the effects of blood pressure lowering treatments for the prevention of dementia and cognitive decline in patients with hypertension but no history of cerebrovascular disease. SEARCH STRATEGY: The trials were identified through a search of CDCIG's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO and CINAHL on 27 April 2005. SELECTION CRITERIA: Randomized, double-blind, placebo controlled trials in which pharmacological or non-pharmacological interventions to lower blood pressure were given for at least six months. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed trial quality and extracted data. The following outcomes were assessed: incidence of dementia, cognitive change from baseline, blood pressure level, incidence and severity of side effects and quality of life. MAIN RESULTS: Three trials including 12,091 hypertensive subjects were identified. Average age was 72.8 years. Participants were recruited from industrialised countries. Mean blood pressure at entry across the studies was 170/84 mmHg. All trials instituted a stepped care approach to hypertension treatment, starting with a calcium-channel blocker, a diuretic or an angiotensin receptor blocker. The combined result of the three trials reporting incidence of dementia indicated no significant difference between treatment and placebo (Odds Ratio (OR) = 0.89, 95% CI 0.69, 1.16). Blood pressure reduction resulted in a 11% relative risk reduction of dementia in patients with no prior cerebrovascular disease but this effect was not statistically significant (p = 0.38) and there was considerable heterogeneity between the trials. The combined results from the two trials reporting change in Mini Mental State Examination (MMSE) did not indicate a benefit from treatment (Weighted Mean Difference (WMD) = 0.10, 95% CI -0.03, 0.23). Both systolic and diastolic blood pressure levels were reduced significantly in the two trials assessing this outcome (WMD = -7.53, 95% CI -8.28, -6.77 for systolic blood pressure, WMD = -3.87, 95% CI -4.25, -3.50 for diastolic blood pressure). Two trials reported adverse effects requiring discontinuation of treatment and the combined results indicated a significant benefit from placebo (OR = 1.18, 95% CI 1.06, 1.30). When analysed separately, however, more patients on placebo in SCOPE were likely to discontinue treatment due to side effects; the converse was true in SHEP 1991. Quality of life data could not be analysed in the three studies. There was difficulty with the control group in this review as many of the control subjects received antihypertensive treatment because their blood pressures exceeded pre-set values. In most cases the study became a comparison between the study drug against a usual antihypertensive regimen. AUTHORS' CONCLUSIONS: There was no convincing evidence from the trials identified that blood pressure lowering prevents the development of dementia or cognitive impairment in hypertensive patients with no apparent prior cerebrovascular disease. There were significant problems identified with analysing the data, however, due to the number of patients lost to follow-up and the number of placebo patients given active treatment. This introduced bias. More robust results may be obtained by analysing one year data to reduce differential drop-out or by conducting a meta-analysis using individual patient data.

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland.

Genetic variation in one of the major APOE receptors in the brain has been associated with increased risk for Alzheimer disease (AD). A C/T polymorphism in exon 3 and a tetranucleotide repeat polymorphism in the 5' region of the low-density lipoprotein receptor-related protein gene have been reported to increase risk in some studies but these reports have not been universally replicated. In addition, genetic variation in another ligand of LRP, alpha-2 macroglobulin (A2M), has also been associated with increased AD risk. However, these reports also remain controversial. We have genotyped both LRP polymorphisms and two polymorphisms in the A2M gene in a large group of clinically well-defined AD cases and controls from the relatively genetically homogeneous Northern Ireland population. Comparison of genotype and allele frequencies for polymorphisms in LRP revealed no significant differences between cases and controls. Multiple logistic regression analysis performed to assess any possible interaction between LRP and APOE revealed little evidence for genetic interaction despite the obvious biological interaction. Genotype and allele comparisons between the groups for the A2M polymorphisms also gave no evidence that either polymorphism increased risk for disease. The results from this study indicate that polymorphisms in LRP and A2M are not associated with increased risk for AD in Northern Ireland.

Myeloperoxidase G-463A polymorphism and Alzheimer's disease in the ApoEurope study.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Epidemiological and molecular genetic studies have shown the existence of several genes associated with increased risk of AD, the major genetic susceptibility locus coding for apolipoprotein E (apoE). A polymorphism in the myeloperoxidase gene (MPO) has previously been associated with AD susceptibility. However, results in the literature are controversial and seem to be dependent on several factors such as gender, apoE polymorphism or the genetic structure of the population. We investigated MPO G-463A and apoE polymorphism in 265 cases and 246 controls from the ApoEurope Study. In females, we found a significant association between MPO genotype and AD (P=0.034), GG genotype frequency being lower in cases (52.4%) as compared to controls (64.2%). In men, there was no significant effect of MPO polymorphism. No interaction was found between MPO polymorphism and apoE epsilon 4 allele. In conclusion, the G-463A polymorphism of MPO was statistically associated with AD in a gender-specific manner. However, given the low significance of P value we suggest no causal effect of the MPO gene in AD, as also evidenced in a recent meta-analysis. Our results support the hypothesis of a possible linkage disequilibrium between the MPO G-463A gene polymorphism and another functional variant involved in AD.

Independent encoding of surface orientation and surface curvature.

Marr [(1982) Vision, San Francisco, Calif.: Freeman] proposed that we represent surface geometry in terms of a viewer-centred description of surface orientation and distance. This description is computed by a range of independent processing systems which take as input particular kinds of information present in images, like surface texture, shading, retinal disparity and motion parallax. The outputs of these modules are integrated in order to provide a unitary representation of the layout of visible surfaces. Higher order properties of surface geometry, like surface curvature, might be computed from this symbolic representation or might be encoded independently from the visual information available at the retinae. We measured surface slant and surface curvature discrimination thresholds for surface patches defined by shading, texture and retinal disparity as a function of the elevation of the illumination. We found that observers judgements about the curvature of local surface patches were too precise to be based on a symbolic representation of surface orientation and we conclude that surface curvature is computed directly from depth cues present in the retinal images.

In pursuit of rational drug use and effective drug management: clinical and public health pharmacy viewpoint.

Drugs are major technology in preventing and combating disease both at the individual and community levels. Managing this valuable resource for optimum public health benefit is paramount. Pharmacists have been recognized by the World Health Organisation and others as having a key role to play in promoting rational drug use and strengthening effective drug management. However, the profession needs to answer some critical questions relating to effective communication of their clinical role. Factors associated with the primary care role of pharmacists are discussed and include education, social and political pressures and professional attitudes. There is evidence of an expanding role for pharmacy in the health sector and a number of new challenges for pharmacy's role in strengthening public health are emerging. These include the profession's involvement in overcoming chronic shortages of essential drugs, strategies to combat the fake and inferior quality drug problems, and increased efforts to educate the public in optimal drug therapy and compliance with recognized drug dosages. Pharmacists are urged to assist governments develop effective policies and legislations for the pharmaceutical sector, based on research findings of pharmaceutical issues affecting public health.

Souvenaid®: a new approach to management of early Alzheimer's disease.

Synaptic loss correlates closely with cognitive deficits in Alzheimer's disease and represents a new target for intervention. Souvenaid® is the first medical nutrition product to be designed to support synapse formation and function in early Alzheimer's disease, and has undergone an extensive, 12-year development programme. The relatively large amount of clinical data available for Souvenaid® is unusual for a medical nutrition product. Souvenaid® contains omega-3 polyunsaturated fatty acids (docosahexaenoic acid and eicosapentaenoic acid), uridine (as uridine monophosphate) and choline which are nutritional precursors required for synaptic membrane phospholipid synthesis, together with phospholipids and other cofactors. Souvenaid® has demonstrated cognitive benefits in patients with mild Alzheimer's disease but not in patients with mild-to-moderate Alzheimer's disease. Two randomised, double-blind, controlled trials (duration 12 and 24 weeks) in patients with mild Alzheimer's disease untreated with acetylcholinesterase inhibitors and/or memantine have demonstrated that Souvenaid® is well tolerated and improves episodic memory performance. The daily intake of Souvenaid® has not been associated with any harmful effects or interactions with medications and none are anticipated. The ongoing, 24-month, European Union-funded LipiDiDiet trial in subjects with prodromal Alzheimer's disease is evaluating the potential benefits of Souvenaid® on memory and in slowing progression to Alzheimer's dementia. If Souvenaid® induces synaptogenesis and improved synaptic function, it may provide benefits in other clinical conditions characterised by neurodegeneration. A number of trials are ongoing and planned to evaluate the potential wider benefits of Souvenaid®.

A User Study on Curved Edges in Graph Visualization.

Recently there has been increasing research interest in displaying graphs with curved edges to produce more readable visualizations. While there are several automatic techniques, little has been done to evaluate their effectiveness empirically. In this paper we present two experiments studying the impact of edge curvature on graph readability. The goal is to understand the advantages and disadvantages of using curved edges for common graph tasks compared to straight line segments, which are the conventional choice for showing edges in node-link diagrams. We included several edge variations: straight edges, edges with different curvature levels, and mixed straight and curved edges. During the experiments, participants were asked to complete network tasks including determination of connectivity, shortest path, node degree, and common neighbors. We also asked the participants to provide subjective ratings of the aesthetics of different edge types. The results show significant performance differences between the straight and curved edges and clear distinctions between variations of curved edges.

A Multiple Indicators Multiple Causes (MIMIC) model of Behavioural and Psychological Symptoms in Dementia (BPSD).

INTRODUCTION: Although there is evidence for distinct behavioural sub-phenotypes in Alzheimer's disease (AD), their inter-relationships and the effect of clinical variables on their expression have been little investigated. METHODS: We have analysed a sample of 1850 probable AD patients from the UK and Greece with 10 item Neuropsychiatric Inventory (NPI) data. We applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of MMSE, disease duration, gender, age and age of onset on the structure of a four-factor model consisting of "psychosis", "moods", "agitation" and "behavioural dyscontrol". RESULTS: Specific clinical variables predicted the expression of individual factors. When the inter-relationship of factors is modelled, some previously significant associations are lost. For example, lower MMSE scores predict psychosis, agitation and behavioural dyscontrol factors, but psychosis and mood predict the agitation factor. Taking these associations into account MMSE scores did not predict agitation. CONCLUSIONS: The complexity of the inter-relations between symptoms, factors and clinical variables is efficiently captured by this MIMIC model.

Perception of fragmented images of three-dimensional objects as the observation angle changes.

Recognition thresholds for incomplete two-dimensional images of three-dimensional objects were measured as the observation angle was changed. A new experimental psychophysical method was developed and programmed for this purpose, this being a modification of the Gollin test, which measures perception thresholds of incomplete outline images. After training to a stimulus alphabet, observers' responses were found to be invariant to changes in the observation angles of three-dimensional objects from 15 degrees to 60 degrees. It is suggested that possible algorithms for the formation of models of three-dimensional images in the human visual system do not operate on the basis of simple section, but involve invariance mechanisms.

Shape from shading. I: Surface curvature and orientation.

The human visual system makes effective use of shading alone in recovering the shape of objects. Pictures of sculptures are readily interpreted--a situation where shading provides virtually the sole cue to shape. However, shading has been considered a poor cue to depth in comparison with retinal disparity and kinetic cues. Curvature discrimination thresholds were measured with the use of a surface-alignment task for a range of surface curvatures from 0.16 cm-1 to 1.06 cm-1. Weber fractions were around 0.1, demonstrating considerable precision in this task. Weber fractions did not vary substantially as a function of surface curvature. Rotation of the light source around the line of sight had no effect on curvature discrimination but rotation towards the viewer increased discrimination thresholds. In contrast, slant discrimination declined with rotation of the light-source vector towards the viewpoint. When a band-limited random grey-level texture was mapped onto the sphere, curvature discrimination thresholds increased gradually as a function of texture contrast, even though texture and shading provided consistent cues to depth. Adding texture also increased slant discrimination thresholds, demonstrating that texture can act as a source of noise in shape-from-shading tasks. The psychophysical findings have been used to evaluate whether current algorithms for shape from shading in computer vision could serve as models of human three-dimensional shape analysis and to highlight low-level intramodular interactions between depth cues. It is demonstrated that, in the case of surfaces defined by shading, curvature descriptions are primary and do not depend upon the prior encoding of surface orientation, and Koenderink's local-shape index is suggested as an alternative intermediate representation of surface shape in the human visual system.