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1.  Physical Activity and Cognitive Trajectories in Cognitively Normal Adults: The Adult Children Study 
Increased physical activity may protect against cognitive decline, the primary symptom of Alzheimer's disease (AD). In this study, we examined the relationship between physical activity and trajectories of cognitive functioning over serial assessments. Cognitively normal (Clinical Dementia Rating 0) middle aged and older adults (N=173, mean age 60.7 +/- 7.8 years) completed a self-report measure of physical activity and a battery of standard neuropsychological tests assessing processing speed, attention, executive functioning, and verbal memory. At baseline, individuals with higher physical activity levels performed better on tests of episodic memory and visuospatial functioning. Over subsequent follow-up visits, higher physical activity was associated with small performance gains on executive functioning and working memory tasks in participants with one or more copy of the apolipoprotein ε4 allele (APOE4). In APOE4 non-carriers, slopes of cognitive performance over time were not related to baseline physical activity. Our results suggest that cognitively normal older adults who report higher levels of physical activity may have slightly better cognitive performance, but the potential cognitive benefits of higher levels of physical activity over time may be most evident in individuals at genetic risk for AD.
PMCID: PMC3778080  PMID: 23739296
Alzheimer's disease; dementia; memory; physical activity; exercise; apolipoprotein E
2.  CSF biomarkers of Alzheimer disease 
Neurology  2013;81(23):2028-2031.
To test whether CSF Alzheimer disease biomarkers (β-amyloid 42 [Aβ42], tau, phosphorylated tau at threonine 181 [ptau181], tau/Aβ42, and ptau181/Aβ42) predict future decline in noncognitive outcomes among individuals cognitively normal at baseline.
Longitudinal data from participants (N = 430) who donated CSF within 1 year of a clinical assessment indicating normal cognition and were aged 50 years or older were analyzed. Mixed linear models were used to test whether baseline biomarker values predicted future decline in function (instrumental activities of daily living), weight, behavior, and mood. Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination scores were also examined.
Abnormal levels of each biomarker were related to greater impairment with time in behavior (p < 0.035) and mood (p < 0.012) symptoms, and more difficulties with independent activities of daily living (p < 0.012). However, biomarker levels were unrelated to weight change with time (p > 0.115). As expected, abnormal biomarker values also predicted more rapidly changing Mini-Mental State Examination (p < 0.041) and Clinical Dementia Rating Sum of Boxes (p < 0.001) scores compared with normal values.
CSF biomarkers among cognitively normal individuals are associated with future decline in some, but not all, noncognitive Alzheimer disease symptoms studied. Additional work is needed to determine the extent to which these findings generalize to other samples.
PMCID: PMC3854826  PMID: 24212387
3.  Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study 
Lancet neurology  2013;12(10):957-965.
New research criteria for preclinical Alzheimer’s disease (AD)have been proposed by the National Institute on Aging and Alzheimer’s Association. They include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and injury markers (stage 2) and abnormal amyloid and injury markers and subtle cognitive changes (stage 3). We investigated the occurrence and long-term outcome of these stages.
Cerebrospinal fluidamyloid-β1–42 and tau levels and a memory composite score were used to classify 311 cognitively normal(Clinical Dementia Rating [CDR]=0) research participants ≥65 years as normal (both markers normal), preclinical AD stage 1–3, or Suspected Non-Alzheimer Pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). Outcome measures were progression to CDR≥0·5 symptomatic AD and mortality up to 15 years after baseline (average=4 years).
129 (41·5%) of participants were normal, 47 (15%)were in stage 1, 36 (12%) in stage 2, 13 (4%)in stage 3, 72 (23%) had SNAP, and 14 (4·5%) remained unclassified. The proportion of preclinical AD (stage 1–3) in our cohort was higher in individuals older than 72 years and in APOE-ε4 carriers. The 5-year progression rate to CDR≥0·5 symptomatic AD was 2% for normal participants, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with normal individuals, participants with preclinical AD had an increased risk of death (HR=6·2, p=0·0396).
Preclinical AD is common in cognitively normal elderly and strongly associated with future cognitive decline and mortality. Preclinical AD thus should be an important target for therapeutic interventions.
PMCID: PMC3904678  PMID: 24012374
4.  Preclinical Alzheimer disease and risk of falls 
Neurology  2013;81(5):437-443.
We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ42, tau, and phosphorylated tau.
We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ42 and CSF phosphorylated tau/Aβ42, after adjustment for common fall risk factors.
The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall.
Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.
PMCID: PMC3776538  PMID: 23803314
5.  Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later 
Neurology  2013;80(19):1784-1791.
We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years.
Longitudinal data from Knight Alzheimer's Disease Research Center participants (N = 201) followed for a mean of 3.70 years (SD = 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. “Expanded” models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared.
Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p > 0.074), nor did we find differences between the expanded biomarker models (p > 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p < 0.005).
Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms.
PMCID: PMC3719431  PMID: 23576620
6.  Cerebrospinal Fluid Biomarkers, Education, Brain Volume and Future Cognition 
Archives of neurology  2011;68(9):1145-1151.
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.
Longitudinal cohort study.
Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.
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).
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.
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.
PMCID: PMC3203689  PMID: 21911695
7.  Role of family history for Alzheimer biomarker abnormalities in the adult children study 
Archives of Neurology  2011;68(10):1313-1319.
To assess whether family history (FH) of Alzheimer’s disease (AD) alone influences AD biomarker abnormalities.
Adult Children Study (ACS).
Washington University's Knight Alzheimer's Disease Research Center.
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).
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.
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.
PMCID: PMC3327304  PMID: 21987546
8.  PIB Imaging Predicts Progression from Cognitively Normal to Symptomatic Alzheimer’s Disease 
Archives of neurology  2009;66(12):1469-1475.
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.
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).
Alzheimer’s Disease Research Center
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).
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.
Preclinical AD, as detected by PET PIB, is not benign as it is associated with progression to symptomatic AD.
PMCID: PMC2798814  PMID: 20008650
9.  Long-term cognitive decline in older subjects was not attributable to non-cardiac surgery or major illness 
Anesthesiology  2009;111(5):964-970.
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.
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.
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.
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.
PMCID: PMC2783989  PMID: 19786858
10.  Driving Retirement in Older Adults with Dementia 
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.
PMCID: PMC2805829  PMID: 20161565
Alzheimer’s disease; driving retirement; automobile driving
11.  Education and Reported Onset of Symptoms among Individuals with Alzheimer’s Disease 
Archives of neurology  2008;65(1):108-111.
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.
Case series.
National Alzheimer’s Coordinating Center Minimum Data Set (N=21,880 participants) and Washington University Alzheimer’s Disease Research Center (N=1,449 participants).
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.
Symptoms of AD are recognized later among those with less education.
PMCID: PMC2830808  PMID: 18195147
12.  Alzheimer’s and Cognitive Reserve 
Archives of neurology  2008;65(11):1467-1471.
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.
[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.
These results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathology and cognition.
PMCID: PMC2752218  PMID: 19001165
13.  Cardiac expression patterns of endothelin-converting enzyme (ECE): Implications for conduction system development 
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.
PMCID: PMC2596959  PMID: 18489007
chick embryo; heart development; immunohistochemistry; endothelin signaling; ventricular conduction system; Purkinje fibers; bosentan
14.  Vulnerability and access to care for South Asian Sikh and Muslim patients with life limiting illness in Scotland: prospective longitudinal qualitative study 
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.
PMCID: PMC2636416  PMID: 19190015
15.  Health in Africa 
BMJ : British Medical Journal  2005;331(7521):904.
PMCID: PMC1255809  PMID: 16223832
16.  Dying from cancer in developed and developing countries: lessons from two qualitative interview studies of patients and their carers 
BMJ : British Medical Journal  2003;326(7385):368.
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.
Scotland: longitudinal study with qualitative interviews. Kenya: cross sectional study with qualitative interviews.
Lothian region, Scotland, and Meru District, Kenya.
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.
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.
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
PMCID: PMC148895  PMID: 12586671

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