Metal-catalyzed oxidative damage and oligomerization of the amyloid-β peptide of Alzheimer’s disease

The most common form of dementia in old age is Alzheimer’s disease (AD). The presence in the brain of senile plaque is the major pathological marker of AD. The plaques are primarily composed of aggregated amyloid-β peptide (Aβ). Aβ is a 40–42 amino acid peptide that is a proteolytic product derived from the β-amyloid precursor protein. The function of Aβ and the exact mechanism of Aβ aggregation and neurotoxicity are unclear. However, metal coordination by Aβ plays an important role in inducing aggregation and the generation of reactive oxygen species, which appears to be at least partially responsible for Aβ neurotoxicity. In this review we examine the role of copper and zinc ions in Aβ neurotoxicity, especially with regards to the generation of free radicals. We discuss the role of copper or zinc ions in oxidative damage and Aβ conformational changes and the relationship of these metals to AD.

Passing time in Clifton Court : an ethnographic study of a unit for confused older people

An exploration of how the residents of a 30 bed unit for confused older people spent their time and a description of the impact upon this of any associated factors. The study demonstrates that it is possible for for elders with dementia and mental health problems to enjoy a range of activities, however, these need to be individualised to take into account the skills they have to meet the challenges with which they are presented. The informed contribution from the activities personnel and the support of nurses is vital to ensure a high quality of social interaction. Sound leadership at the clinical level is essential.

Metaphors, stigma and the ‘Alzheimerization’ of the euthanasia debate

This paper reports the findings of an unobtrusive research inquiry investigating the possible use and misuse of Alzheimer’s disease in public policy debate on the legalization of euthanasia. The component of the study being reported identified the problematic use of five key metaphors: the Alzheimer metaphor, which in turn was reinforced by three additional metaphors – the epidemic metaphor, the military metaphor, and the predatory thief metaphor; and the euthanasia metaphor. All metaphors were found to be morally loaded and used influentially to stigmatize Alzheimer’s disease and mediate public opinion supporting the legalization of euthanasia as an end-of-life ‘solution’ for people with the disease. It is contended that, in the interests of promoting intellectual honesty and giving proper recognition to the extraordinary complexity of the issue, the problematic use and influence of metaphoric thinking in the public debate about Alzheimer’s disease and euthanasia needs to be made transparent, questioned and challenged.

Altered intracellular localization and valosin-containing protein (p97 VCP) interaction underlie ATP7A-related distal motor neuropathy

ATP7A is a P-type ATPase that regulates cellular copper homeostasis by activity at the trans-Golgi network (TGN) and plasma membrane (PM), with the location normally governed by intracellular copper concentration. Defects in ATP7A lead to Menkes disease or its milder variant, occipital horn syndrome or to a newly discovered condition, ATP7A-related distal motor neuropathy (DMN), for which the precise pathophysiology has been obscure. We investigated two ATP7A motor neuropathy mutations (T994I, P1386S) previously associated with abnormal intracellular trafficking. In the patients' fibroblasts, total internal reflection fluorescence microscopy indicated a shift in steady-state equilibrium of ATP7AT994I and ATP7AP1386S, with exaggerated PM localization. Transfection of Hek293T cells and NSC-34 motor neurons with the mutant alleles tagged with the Venus fluorescent protein also revealed excess PM localization. Endocytic retrieval of the mutant alleles from the PM to the TGN was impaired. Immunoprecipitation assays revealed an abnormal interaction between ATP7AT994I and p97/VCP, an ubiquitin-selective chaperone which is mutated in two autosomal dominant forms of motor neuron disease: amyotrophic lateral sclerosis and inclusion body myopathy with early-onset Paget disease and fronto-temporal dementia. Small-interfering RNA (SiRNA) knockdown of p97/VCP corrected ATP7AT994I mislocalization. Flow cytometry documented that non-permeabilized ATP7AP1386S fibroblasts bound a carboxyl-terminal ATP7A antibody, consistent with relocation of the ATP7A di-leucine endocytic retrieval signal to the extracellular surface and partially destabilized insertion of the eighth transmembrane helix. Our findings illuminate the mechanisms underlying ATP7A-related DMN and establish a link between p97/VCP and genetically distinct forms of motor neuron degeneration.

Cognitive impairment and vitamin B12 : a review

Background: This review examines the associations between low vitamin B12 levels, neurodegenerative disease, and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12 therapy is efficacious for cognitive impairment and dementia.

Methods: A systematic literature search identified 43 studies investigating the association of vitamin B12 and cognitive impairment or dementia. Seventeen studies reported on the efficacy of vitamin B12 therapy for these conditions.

Results: Vitamin B12 levels in the subclinical low-normal range (<250 ρmol/L) are associated with Alzheimer's disease, vascular dementia, and Parkinson's disease. Vegetarianism and metformin use contribute to depressed vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deficiency (<150 ρmol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily) were effective in correcting biochemical deficiency, but improved cognition only in patients with pre-existing vitamin B12 deficiency (serum vitamin B12 levels <150 ρmol/L or serum homocysteine levels >19.9 μmol/L).

Conclusion: Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-existing deficiency. There is a need for large, well-resourced clinical trials to close the gaps in our current understanding of the nature of the associations of vitamin B12 insufficiency and neurodegenerative disease.

Oiling the brain : a review of randomized controlled trials of omega-3 fatty acids in psychopathology across the lifespan

Around one in four people suffer from mental illness at some stage in their lifetime. There is increasing awareness of the importance of nutrition, particularly omega-3 polyunsaturated fatty acids (n-3 PUFA), for optimal brain development and function. Hence in recent decades, researchers have explored effects of n-3 PUFA on mental health problems over the lifespan, from developmental disorders in childhood, to depression, aggression, and schizophrenia in adulthood, and cognitive decline, dementia and Alzheimer’s disease in late adulthood. This review provides an updated overview of the published and the registered clinical trials that investigate effects of n-3 PUFA supplementation on mental health and behavior, highlighting methodological differences and issues.

Managing older people with type 2 diabetes

The Guideline for Managing Older People with Type 2 Diabetes was considered a necessary development following the launch of the IDF 2012 Global Guideline for Type 2 Diabetes. In the latter, recommendations for managing diabetes in older people were included for the first time by the IDF but the review group felt that there were many areas where specific advice was still needed and indeed would offer the clinician extra value in decision making. It was also felt that the format of recommendation in the 2012 Guideline did not offer the flexibility required to address the special issues of older people and their varied physical, cognitive, and social needs.

An international group of diabetes experts was assembled to consider the key issues that require attention in supporting the highest quality of diabetes care for older people on a global scale. This Guideline is unique as it has been developed to provide the clinician with recommendation that assist in clinical management of a wide range of older adults such as those who are not only relatively well and active but those who are functionally dependent. This latter group has been categorised as those with frailty, or dementia, or those at the end of life. We have included practical advice on assessment measures that enable the clinician to categorise all older adults with diabetes and allow the appropriate and relevant recommendations to be applied.

The Guideline has been structured into main chapter headings dealing with expected areas such as cardiovascular risk, education, renal impairment, diabetic foot disease and so on, but also includes commonly addressed areas such as seen such as sexual health. Also included is a section of 'special consideration' where areas such as pain and end of life care are addressed.

Advance care planning for older people in Australia presenting to the emergency department from the community or residential aged care facilities

The purpose of this retrospective, cross-sectional study was to determine the prevalence of advance care planning (ACP) among older people presenting to an Emergency Department (ED) from the community or a residential aged care facility. The study sample comprised 300 older people (aged 65+ years) presenting to three Victorian EDs in 2011. A total of 150 patients transferred from residential aged care to ED were randomly selected and then matched to 150 people who lived in the community and attended the ED by age, gender, reason for ED attendance and triage category on arrival. Overall prevalence of ACP was 13.3% (n = 40/300); over one-quarter (26.6%, n = 40/150) of those presenting to the ED from residential aged care had a documented Advance Care Plan, compared to none (0%, n = 0/150) of the people from the community. There were no significant differences in the median ED length of stay, number of investigations and interventions undertaken in ED, time seen by a doctor or rate of hospital admission for those with an Advance Care Plan compared to those without. Those with a comorbidity of cerebrovascular disease or dementia and those assessed with impaired brain function were more likely to have a documented Advance Care Plan on arrival at ED. Length of hospital stay was shorter for those with an Advance Care Plan [median (IQR) = 3 days (2–6) vs. 6 days (2–10), P = 0.027] and readmission lower (0% vs. 13.7%). In conclusion, older people from the community transferred to ED were unlikely to have a documented Advance Care Plan. Those from residential aged care who were cognitively impaired more frequently had an Advance Care Plan. In the ED, decisions of care did not appear to be influenced by the presence or absence of Advance Care Plans, but length of hospital admission was shorter for those with an Advance Care Plan.

Indications for computed tomographic brain scanning in psychiatric inpatients.

This study examined the rate of use of computed tomographic (CT) scanning as well as clinical parameters pertaining to that used in psychiatric patients. These patients were compared with a randomly selected control group of psychiatric patients who were not scanned. In addition, scan abnormalities were examined and correlated with clinical and electro-encephalographic (EEG) data. CT scanning was used on 13.5% of admissions. On axis 1 of the DSM III-R, the CT scan group had a significantly higher incidence of delirium and dementia (P < 0.05) and a much higher rate of medical illness (P < 0.01) on axis 3. The rate of CT abnormality was fairly high at 45.2%. An abnormal CT scan was associated with the diagnosis of dementia, the presence of organic mental status abnormality and of abnormality on neurological examination. Focally abnormal CT scans were associated with focally abnormal EEGs in a significant number of patients (P < 0.05).

Blood pressure and cognitive function: the role of central aortic and brachial pressures

Central (aortic) blood pressures differ from brachial pressures and may be more relevant to the study of cognitive function, given that blood is delivered to the brain through the central large arteries. Pulse-pressure amplification reflects the augmentation of blood pressure between the central and peripheral arteries, which diminishes with aging. We aimed to determine the association between central blood pressure and cognitive function in independently living adults aged 20 to 82 years (N = 493). In adjusted regression models, higher central systolic pressure and higher central pulse pressure were each associated with poorer processing speed, Stroop processing, and recognition memory. Lower amplification was associated with poorer Stroop processing, working memory, and recognition memory. Higher brachial systolic pressure and brachial pulse pressure were both associated with poorer Stroop processing. In summary, central pressures and amplification were sensitive indicators of cognitive aging, predicting aspects of cognitive performance not predicted by brachial blood pressure.

Improved processing speed: online computer-based cognitive training in older adults

In an increasingly aging population, a number of adults are concerned about declines in their cognitive abilities. Online computer-based cognitive training programs have been proposed as an accessible means by which the elderly may improve their cognitive abilities; yet, more research is needed in order to assess the efficacy of these programs. In the current study, a commercially available 21-day online computer-based cognitive training intervention was administered to 34 individuals aged between 53 and 75 years. The intervention consisted of computerized training in reaction time, inspection time, short-term memory for words, executive function, visual spatial acuity, arithmetic, visual spatial memory, visual scanning/discrimination, and n-back working memory. An active solitaire control group was also included. Participants were tested at baseline, posttraining and at three-weeks follow-up using a battery of neuropsychological outcome measures. These consisted of simple reaction time, complex reaction time, digit forwards and backwards, spatial working memory, digit symbol substitution, RAVLT, and trail making. Significant improvement in simple reaction time and choice reaction time task was found in the cognitive training group both posttraining and at three-weeks follow-up. However, no significant improvements on the other cognitive tasks were found. The training program was found to be successful in achieving transfer of trained cognitive abilities in speed of processing to similar untrained tasks. © 2012 Copyright Taylor and Francis Group, LLC.