Delirium in early-stage Alzheimer's disease : enhancing cognitive reserve as a possible preventive measure

Delirium is a disorder of acute onset with fluctuating symptoms and is characterized by inattention, disorganized thinking, and altered levels of consciousness. The risk for delirium is greatest in individuals with dementia, and the incidence of both is increasing worldwide because of the aging of our population. Although several clinical trials have tested interventions for delirium prevention in individuals without dementia, little is known about the mechanisms for the prevention of delirium in early-stage Alzheimer’s disease (AD). The purpose of this article is to explore ways of preventing delirium and slowing the rate of cognitive decline in early-stage AD by enhancing cognitive reserve. An agenda for future research on interventions to prevent delirium in individuals with early-stage AD is also presented.

A Survey-based Study of Knowledge of Alzheimer's Disease among Health Care Staff

Background Continued aging of the population is expected to be accompanied by substantial increases in the number of people with dementia and in the number of health care staff required to care for them. Adequate knowledge about dementia among health care staff is important to the quality of care delivered to this vulnerable population. The purpose of this study was to assess knowledge about dementia across a range of health care staff in a regional health service district. Methods Knowledge levels were investigated via the validated 30-item Alzheimer's Disease Knowledge Scale (ADKS). All health service district staff with e-mail access were invited to participate in an online survey. Knowledge levels were compared across demographic categories, professional groups, and by whether the respondent had any professional or personal experience caring for someone with dementia. The effect of dementia-specific training or education on knowledge level was also evaluated. Results A diverse staff group (N = 360), in terms of age, professional group (nursing, medicine, allied health, support staff) and work setting from a regional health service in Queensland, Australia responded. Overall knowledge about Alzheimer's disease was of a generally moderate level with significant differences being observed by professional group and whether the respondent had any professional or personal experience caring for someone with dementia. Knowledge was lower for some of the specific content domains of the ADKS, especially those that were more medically-oriented, such as 'risk factors' and 'course of the disease.' Knowledge was higher for those who had experienced dementia-specific training, such as attendance at a series of relevant workshops. Conclusions Specific deficits in dementia knowledge were identified among Australian health care staff, and the results suggest dementia-specific training might improve knowledge. As one piece of an overall plan to improve health care delivery to people with dementia, this research supports the role of introducing systematic dementia-specific education or training.

Perceptions of stressors and reported coping strategies in nurses caring for residents with Alzheimer's disease in a dementia unit

A study was undertaken on the perceptions of stressors and coping behaviours in a group of nurses caring for residents with Alzheimer's disease in a dementia unit. The purpose of this paper is to report on the preliminary findings of the study. Repertory grid data were used to explore how nurses perceive residents, the stressors nurses experience in their work, and the coping strategies nurses use when caring for residents. The nurses identified 92 sources of stress, 683 coping behaviours and 708 coping strategies. Analyses of selected repertory grid data are presented and the stressors reported by the nurses are summarized. The coping strategies the nurses report using are classified into categories of adaptive and maladaptive responses to stress. In addition, the nursing implications of the coping strategies used by the nurses are also considered.

Current treatment for Alzheimer's disease : an overview

Despite extensive research, no cure has been found for Alzheimer's disease as yet. A large number of medications have been investigated to determine their potential for altering the natural history of the disease and this work is ongoing. In an effort to shed light on current and future (awaiting approval) medications, the following is a summary of published material and experiences with some of the drugs.

Protein markers for Alzheimer disease in the frontal cortex and cerebellum

Objective: To compare proteins related to Alzheimer disease ( AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset AD ( LOAD) and nondemented control subjects. Methods: Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain. Results: In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Abeta) deposition (by immunohistochemistry), increased soluble Abeta (by immunoblot analysis), and specific increases in Abeta(40) and Abeta(42) ( by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Abeta, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein beta-catenin levels were unchanged. Conclusions: This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.

Current dementia research in Australia : a report from the Alzheimer's Australia 15th National Conference

The Alzheimer’s Australia 15th National Conference held on 14–17 May 2013 in Hobart (Tasmania, Australia) attracted a wide range of attendees, including people living with dementia, family caregivers, health professionals and researchers. The conference theme, The Tiles of Life Coloring the Future, invoking a vision of a better future for those affected by dementia, had seven subthemes: liberation, rehabilitation, leisure,service, creativity, wellbeing and research.

Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults

There is a strong genetic risk for late-onset Alzheimer's disease (AD), but so far few gene variants have been identified that reliably contribute to that risk. A newly confirmed genetic risk allele C of the clusterin (CLU) gene variant rs11136000 is carried by ~88% of Caucasians. The C allele confers a 1.16 greater odds of developing late-onset AD than the T allele. AD patients have reductions in regional white matter integrity. We evaluated whether the CLU risk variant was similarly associated with lower white matter integrity in healthy young humans. Evidence of early brain differences would offer a target for intervention decades before symptom onset. We scanned 398 healthy young adults (mean age, 23.6 ± 2.2 years) with diffusion tensor imaging, a variation of magnetic resonance imaging sensitive to white matter integrity in the living brain. We assessed genetic associations using mixed-model regression at each point in the brain to map the profile of these associations with white matter integrity. Each C allele copy of the CLUvariant was associated with lower fractional anisotropy-a widely accepted measure of white matter integrity-in multiple brain regions, including several known to degenerate in AD. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. Young healthy carriers of the CLU gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing AD later in life.

Automated ventricular mapping with multi-atlas fluid image alignment reveals genetic effects in Alzheimer's disease

We developed and validated a new method to create automated 3D parametric surface models of the lateral ventricles in brain MRI scans, providing an efficient approach to monitor degenerative disease in clinical studies and drug trials. First, we used a set of parameterized surfaces to represent the ventricles in four subjects' manually labeled brain MRI scans (atlases). We fluidly registered each atlas and mesh model to MRIs from 17 Alzheimer's disease (AD) patients and 13 age- and gender-matched healthy elderly control subjects, and 18 asymptomatic ApoE4-carriers and 18 age- and gender-matched non-carriers. We examined genotyped healthy subjects with the goal of detecting subtle effects of a gene that confers heightened risk for Alzheimer's disease. We averaged the meshes extracted for each 3D MR data set, and combined the automated segmentations with a radial mapping approach to localize ventricular shape differences in patients. Validation experiments comparing automated and expert manual segmentations showed that (1) the Hausdorff labeling error rapidly decreased, and (2) the power to detect disease- and gene-related alterations improved, as the number of atlases, N, was increased from 1 to 9. In surface-based statistical maps, we detected more widespread and intense anatomical deficits as we increased the number of atlases. We formulated a statistical stopping criterion to determine the optimal number of atlases to use. Healthy ApoE4-carriers and those with AD showed local ventricular abnormalities. This high-throughput method for morphometric studies further motivates the combination of genetic and neuroimaging strategies in predicting AD progression and treatment response. © 2007 Elsevier Inc. All rights reserved.

Alzheimer's disease risk gene, GAB2, is associated with regional brain volume differences in 755 young healthy twins

The development of late-onset Alzheimer's disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer's disease risk gene, growth factor receptor bound protein 2-associated protein (GAB2), has been shown to provide a 1.27- 1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young adult twins (469 females) (M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer's disease.

4D deformation modeling of cortical disease progression in Alzheimer's dementia

This work describes the development of a model of cerebral atrophic changes associated with the progression of Alzheimer's disease (AD). Linear registration, region-of-interest analysis, and voxel-based morphometry methods have all been employed to elucidate the changes observed at discrete intervals during a disease process. In addition to describing the nature of the changes, modeling disease-related changes via deformations can also provide information on temporal characteristics. In order to continuously model changes associated with AD, deformation maps from 21 patients were averaged across a novel z-score disease progression dimension based on Mini Mental State Examination (MMSE) scores. The resulting deformation maps are presented via three metrics: local volume loss (atrophy), volume (CSF) increase, and translation (interpreted as representing collapse of cortical structures). Inspection of the maps revealed significant perturbations in the deformation fields corresponding to the entorhinal cortex (EC) and hippocampus, orbitofrontal and parietal cortex, and regions surrounding the sulci and ventricular spaces, with earlier changes predominantly lateralized to the left hemisphere. These changes are consistent with results from post-mortem studies of AD.

Quantitative and qualitative impairments in semantic fluency, but not phonetic fluency, as a potential risk factor for Alzheimer's disease

Qualitative aspects of verbal fluency may be more useful in discerning the precise cause of any quantitative deficits in phonetic or category fluency, especially in the case of mild cognitive impairment (MCI), a possible intermediate stage between normal performance and Alzheimer's disease (AD). The aim of this study was to use both quantitative and qualitative (switches and clusters) methods to compare the phonetic and category verbal fluency performance of elderly adults with no cognitive impairment (n = 51), significant memory impairment (n = 16), and AD (n = 16). As expected, the AD group displayed impairments in all quantitative and qualitative measures of the two fluency tasks relative to their age- and education-matched peers. By contrast, the amnestic MCI group produced fewer animal names on the semantic fluency task than controls and showed normal performance on the phonetic fluency task. The MCI group's inferior category fluency performance was associated with a deficit in their category-switching rate rather than word cluster size. Overall, the results indicate that a semantic measure such as category fluency when used in conjunction with a test of episodic memory may increase the sensitivity for detecting preclinical AD. Future research using external cues and other measures of set shifting capacity may assist in clarifying the origin of the amnestic MCI-specific category-switching deficiency. Copyright

A 1H MRS study of probable Alzheimer's disease and normal aging: Implications for longitudinal monitoring of dementia progression

In order to evaluate the capability of 1H MRS to monitor longitudinal changes in subjects with probable Alzheimer's disease (AD), the temporal stability of the metabolite measures N-acetylaspartate and N- acetylaspartylglutamate (NA), total Creatine (Cr), myo-Inositol (mI), total Choline (Chol), NA/Cr, mI/Cr, Chol/Cr and NA/mI were investigated in a cohort of normal older adults. Only the metabolite measures NA, mI, Cr, NA/Cr, mI/Cr, and NA/mI were found to be stable after a mean interval of 260 days. Relative and absolute metabolite measures from a cohort of patients with probable AD were subsequently compared with data from a sample of normal older adult control subjects, and correlated with mental status and the degree of atrophy in the localized voxel. Concentrations of NA, NA/Cr, and NA/mI were significantly reduced in the AD group with concomitant significant increases in mI and mI/Cr. There were no differences between the two groups in measures of Cr, Chol, or Chol/Cr. Significant correlations between mental status as measured by the Mini-Mental State Examination and NA/mI, mI/Cr and NA were found. These metabolite measures were also significantly correlated with the extent of atrophy (as measured by CSF and GM composition) in the spectroscopy voxel.

Dynamics of gray matter loss in Alzheimer's disease

We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimer's disease (AD). The loss pattern was visualized in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, sparing sensorimotor cortices. The shifting deficits were asymmetric (left hemisphere > right hemisphere) and correlated with progressively declining cognitive status (p < 0.0006). Novel brain mapping methods allowed us to visualize dynamic patterns of atrophy in 52 high-resolution magnetic resonance image scans of 12 patients with AD (age 68.4 ± 1.9 years) and 14 elderly matched controls (age 71.4 ± 0.9 years) scanned longitudinally (two scans; interscan interval 2.1 ± 0.4 years). A cortical pattern matching technique encoded changes in brain shape and tissue distribution across subjects and time. Cortical atrophy occurred in a well defined sequence as the disease progressed, mirroring the sequence of neurofibrillary tangle accumulation observed in cross sections at autopsy. Advancing deficits were visualized as dynamic maps that change over time. Frontal regions, spared early in the disease, showed pervasive deficits later (< 15% loss). The maps distinguished different phases of AD and differentiated AD from normal aging. Local gray matter loss rates (5.3 ± 2.3% per year in AD v 0.9 ± 0.9% per year in controls) were faster in the left hemisphere (p < 0.029) than the right. Transient barriers to disease progression appeared at limbic/frontal boundaries. This degenerative sequence, observed in vivo as it developed, provides the first quantitative, dynamic visualization of cortical atrophic rates in normal elderly populations and in those with dementia.