Objective

To evaluate the combination of cerebrospinal fluid biomarkers of Aβ42, tau, and phosphorylated tau (ptau181) with education and normalized whole brain volume (nWBV) to predict incident cognitive impairment and test the cognitive/brain reserve hypothesis.

Design

Longitudinal cohort study.

Setting

Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.

Participants

Convenience sample of 197 participants aged 50 years and above, with normal cognition (Clinical Dementia Rating [CDR] of 0) at baseline, followed for a mean of 3.3 years.

Main outcome measure

Time to cognitive impairment (CDR ≥ 0.5).

Results

Three-factor interactions between the baseline biomarker values, education, and nWBV were found for Cox proportional hazards models testing tau (p=.03) and ptau (p=.008). Among those with lower tau values, nWBV (hazard ratio [HR]=.54, 95% confidence interval [CI]=.31–.91; p=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (p=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment among those with higher ptau values (p=.02). In models testing Aβ42, larger nWBV was associated with a slower time to cognitive impairment (HR=.84, 95%CI=.71–.99, p=.0348), but there was no effect of Aβ42 or education.

Conclusions

Among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.

Objective

To assess whether family history (FH) of Alzheimer’s disease (AD) alone influences AD biomarker abnormalities.

Design

Adult Children Study (ACS).

Setting

Washington University's Knight Alzheimer's Disease Research Center.

Participants

Cognitively normal middle to older age individuals with and without a FH for AD (n=269).

Main Outcome Measures

Clinical and cognitive measures, magnetic resonance imaging (MRI)-based brain volumes, diffusion tensor imaging (DTI)-based white matter microstructure, cerebrospinal fluid (CSF) biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound-B (PIB).

Results

A positive FH for AD was associated with an age-related decrease of CSF Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted CSF Aβ42 was decreased for individuals with APOE4 compared with those without, and the decrease was larger for individuals with a positive FH compared with those without. The variation of CSF tau and PIB mean cortical binding potential (MCBP) increased by age. For individuals younger than 55, an age-related increase in MCBP was associated with APOE4, but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in MCBP. A positive FH was associated with decreased fractional anisotropy from DTI in the genu and splenium of the corpus callosum.

Conclusion

Independent of APOE4, FH is associated with age-related change of several CSF, PIB and DTI biomarkers in cognitively normal middle to older age individuals, suggesting that non-APOE susceptibility genes for AD influence AD biomarkers.

Objective

To determine whether preclinical Alzheimer’s disease (AD), as detected by the amyloid imaging agent Pittsburgh Compound B (PIB) in cognitively normal older adults, is associated with risk of symptomatic AD.

Design

A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PIB and followed with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT).

Setting

Alzheimer’s Disease Research Center

Participants

One hundred and fifty-nine participants with mean age of 71.5 y in a longitudinal study of memory and aging had a PET PIB scan when cognitively normal with Clinical Dementia Rating (CDR) of 0.

Outcome Measure

Progression from CDR 0 status to CDR 0.5 (very mild dementia).

Results

Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range: 1–5 assessments after PET PIB). Of these, 9 also were diagnosed with DAT. Higher MCBP values for PIB (hazard ratio 4.85, 95% CI, 1.22–19.01, p = .02) and age (hazard ratio 1.14, 95% CI 1.02–1.28, p = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in three cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained CDR 0.

Conclusions

Preclinical AD, as detected by PET PIB, is not benign as it is associated with progression to symptomatic AD.

Background

Persistent postoperative cognitive decline is thought to be a public health problem, but its severity may have been overestimated because of limitations in statistical methodology. This study assessed whether long-term cognitive decline occurred after surgery or illness by using an innovative approach and including participants with early Alzheimer's disease to overcome some limitations.

Methods

In this retrospective cohort study, three groups were identified from participants tested annually at Washington University's Alzheimer Disease Research Center in St. Louis: those with non-cardiac surgery, illness, or neither. This enabled long-term tracking of cognitive function before and after surgery and illness. The effect of surgery and illness on longitudinal cognitive course was analyzed using a general linear mixed effects model. For participants without initial dementia, time to dementia onset was analyzed using sequential Cox proportional hazards regression.

Results

Of the 575 participants, 214 were nondemented and 361 had very mild or mild dementia at enrollment. Cognitive trajectories did not differ among the three groups (surgery, illness, control), although demented participants declined more markedly than nondemented. Of the initially nondemented participants, 23% progressed to a clinical dementia rating greater than zero, but this was not more common following surgery or illness.

Conclusions

The study did not detect long-term cognitive decline independently attributable to surgery or illness nor were these events associated with accelerated progression to dementia. The decision to proceed with surgery in elderly people, including those with early Alzheimer's disease, may presently be made without factoring in the specter of persistent cognitive deterioration.

In order to characterize the driving and mobility status of older adults with dementia, a questionnaire was mailed to 527 informants; 119 were returned. The majority of patients were diagnosed with Dementia of the Alzheimer’s Type. Only 28% were actively driving at the time of survey. Informants rated 53% of current or recently retired drivers as potentially unsafe. Few informants reported using community/educational resources. Individuals with progressive dementia retire from driving for differing reasons, many subsequent to family recognition of impaired driving performance. Opportunities for education and supportive assistance exist but are underutilized.

Objective

To examine whether reported age at onset (AAO) of dementia symptoms among participants with Alzheimer’s disease (AD) is later for those with fewer years of education and, if so, to see if it is attributed to delayed detection of symptoms.

Design

Case series.

Setting

National Alzheimer’s Coordinating Center Minimum Data Set (N=21,880 participants) and Washington University Alzheimer’s Disease Research Center (N=1,449 participants).

Results

Reported AAO of dementia symptoms is slightly earlier for participants with more education. Participants with fewer years of education show greater clinical severity of AD at first assessment.

Conclusion

Symptoms of AD are recognized later among those with less education.

Objective

To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid.

Design, Setting, and Participants

Uptake of N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroybenzothiazole, or [11C]PIB for “Pittsburgh Compound-B,” was measured for participants assessed between August 15, 2003 and January 8, 2008 at the Washington University Alzheimer’s Disease Research Center and diagnosed either as nondemented (N=161) or with dementia of the Alzheimer type (N=37). Multiple regression was used to determine whether [11C]PIB uptake interacted with level of educational attainment to predict cognitive function.

Main Outcome Measures

Scores on the Clinical Dementia Rating - Sum of Boxes (CDR-SB), Mini-Mental State Exam (MMSE), and Short Blessed Test (SBT), and individual measures from a psychometric battery.

Results

[11C]PIB uptake interacted with years of education in predicting scores on the CDR-SB (p=.003), the MMSE (p<.001), the SBT (p=.03) and a measure of verbal abstract reasoning and conceptualization (p=.02), such that performance on these measures increased with increasing education for participants with elevated PIB uptake. Education was unrelated to global cognitive functioning scores among those with lower PIB uptake.

Conclusions

These results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathology and cognition.

The spatiotemporal distribution of the endothelin-converting enzyme (ECE) protein in the embryonic chick heart and the association of this polypeptide with developing cardiac conduction system is described here for the first time. Further, we show how cardiac hemodynamic load directly affects ECE level and distribution. Endothelin (ET) is a cytokine involved in the inductive recruitment of Purkinje fibers. ET is produced by proteolytic cleavage of Big-ET by ECE. We generated an antibody against chick ECE recognizing a single band at ~70 kD to correlate the cardiac expression of this protein with that reported previously for its mRNA. ECE protein expression was more widespread compared to its mRNA, being present in endothelial cells, mesenchymal cells and myocytes, and particularly enriched in the trabeculae and nascent ventricular conduction system. The myocardial expression was significantly modified under experimentally altered hemodynamic loading. In vivo, ET receptor blockade with bosentan delayed activation sequence maturation. These data support a role for ECE in avian cardiac conduction system differentiation and maturation.

Objectives To examine the care experiences of South Asian Sikh and Muslim patients in Scotland with life limiting illness and their families and to understand the reasons for any difficulties with access to services and how these might be overcome.

Design Prospective, longitudinal, qualitative design using in-depth interviews.

Setting Central Scotland.

Participants 25 purposively selected South Asian Sikh and Muslim patients, 18 family carers, and 20 key health professionals.

Results 92 interviews took place. Most services struggled to deliver responsive, culturally appropriate care. Barriers to accessing effective end of life care included resource constrained services; institutional and, occasionally, personal racial and religious discrimination; limited awareness and understanding among South Asian people of the role of hospices; and difficulty discussing death. The most vulnerable patients, including recent migrants and those with poor English language skills, with no family advocate, and dying of non-malignant diseases were at particularly high risk of inadequate care.

Conclusions Despite a robust Scottish diversity policy, services for South Asian Sikh and Muslim patients with life limiting illness were wanting in many key areas. Active case management of the most vulnerable patients and carers, and “real time” support, from where professionals can obtain advice specific to an individual patient and family, are the approaches most likely to instigate noticeable improvements in access to high quality end of life care. Improving access to palliative care for all, particularly those with non-malignant illnesses, as well as focusing on the specific needs of ethnic minority groups, is required.

Objective

To describe the experiences of illness and needs and use of services in two groups of patients with incurable cancer, one in a developed country and the other in a developing country.

Design

Scotland: longitudinal study with qualitative interviews. Kenya: cross sectional study with qualitative interviews.

Settings

Lothian region, Scotland, and Meru District, Kenya.

Participants

Scotland: 20 patients with inoperable lung cancer and their carers. Kenya: 24 patients with common advanced cancers and their main informal carers.

Main outcome measures

Descriptions of experiences, needs, and available services.

Results

67 interviews were conducted in Scotland and 46 in Kenya. The emotional pain of facing death was the prime concern of Scottish patients and their carers, while physical pain and financial worries dominated the lives of Kenyan patients and their carers. In Scotland, free health and social services (including financial assistance) were available, but sometimes underused. In Kenya, analgesia, essential equipment, suitable food, and assistance in care were often inaccessible and unaffordable, resulting in considerable unmet physical needs. Kenyan patients thought that their psychological, social, and spiritual needs were met by their families, local community, and religious groups. Some Scottish patients thought that such non-physical needs went unmet.

Conclusions

In patients living in developed and developing countries there are differences not only in resources available for patients dying from cancer but also in their lived experience of illness. The expression of needs and how they are met in different cultural contexts can inform local assessment of needs and provide insights for initiatives in holistic cancer care.

What is already known on this topic?Cancer treatment is a priority and is well developed in the United KingdomThere is an increasing burden on inadequately funded health services in developing countriesWhat this study addsThe experience of dying from cancer in Scotland contrasts starkly with that experienced in KenyaInequalities in provision of palliative care persist between developed and developing countriesDespite the availability of resources in the United Kingdom, people still have major areas of unmet needsConsideration of patients' experiences and provision of care in contrasting cultural settings can highlight gaps in frameworks of cancer care