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BACKGROUND This paper describes the rationale and design of the ENVIS-ion Study, which aims to determine whether low-dose aspirin reduces the development of white matter hyper-intense (WMH) lesions and silent brain infarction (SBI). Additional aims include determining whether a) changes in retinal vascular imaging (RVI) parameters parallel changes in brain magnetic resonance imaging (MRI); b) changes in RVI parameters are observed with aspirin therapy; c) baseline cognitive function correlates with MRI and RVI parameters; d) changes in cognitive function correlate with changes in brain MRI and RVI and e) whether factors such as age, gender or blood pressure influence the above associations. METHODS/DESIGN Double-blind, placebo-controlled trial of three years duration set in two Australian academic medical centre outpatient clinics. This study will enrol 600 adults aged 70 years and over with normal cognitive function and without overt cardiovascular disease. Subjects will undergo cognitive testing, brain MRI and RVI at baseline and after 3 years of study treatment. All subjects will be recruited from a 19,000-patient clinical outcome trial conducted in Australia and the United States that will evaluate the effects of aspirin in maintaining disability-free longevity over 5 years. The intervention will be aspirin 100 mg daily versus matching placebo, randomized on a 1:1 basis. DISCUSSION This study will improve understanding of the mechanisms at the level of brain and vascular structure that underlie the effects of aspirin on cognitive function. Given the limited access and high cost of MRI, RVI may prove useful as a tool for the identification of individuals at high risk for the development of cerebrovascular disease and cognitive decline. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01038583.

The relationship between body mass index (BMI) (in midlife and late-life) and dementia was investigated in meta-analyses of 16 articles reporting on 15 prospective studies. Follow-ups ranged from 3.2 to 36.0 years. Meta-analyses were conducted on samples

Background: Ideally putative disease-modifying therapies for Alzheimer's disease (AD) should be tested in patients who have minimal morbidity. Current barriers to such trials in early disease include the lack of disease-specific early biomarkers, insensitivity of quantitative cognitive outcome measures, and expensive trial designs requiring large sample sizes and long duration. This paper describes principles and progress towards a novel trial design that overcomes these problems, utilizing wide-scale cognitive performance screening to define pre-trial cognitive decline trajectories which can serve as trial outcome measures to assess AD disease-modifying efficacy. Methods: Theoretical principles important for the detection of intra-individual cognitive decline and a practical example are described. Results: Serial evaluations of community-based volunteers demonstrate how a screening tool method to detect subtle cognitive decline can predict in vivo amyloid pathology as a trigger for etiological evaluation. Trajectories of decline appear consistent over at least two years, suggesting they could be used as a trial inclusion criterion and ameliorable outcome measure together with other AD biomarkers. Informative trial durations could be 6-12 months, or extend to incorporate staggered random withdrawal or start designs, with as few as 20 individuals per treatment arm. Conclusions: This trial methodology offers significant advantages over current AD trial designs, including treatment at earlier stages of disease, shorter trial duration, obviation of informed consent difficulties, smaller sample sizes, reduced cost and - given adequate screening programs - sufficient subjects for multiple simultaneous trials. Importantly, it allows the rapid evaluation of putative treatments that may only be efficacious in pre-dementia states.

While hippocampal volumes have been extensively examined in neuropsychiatric disorders and ageing, small areas of signal variation within the hippocampus commonly observed on MRI, described as hippocampal sulcal cavities (HSCs), have received less attention. We review the published literature on HSCs to examine their prevalence, putative aetiological factors such as hypertension, and possible cognitive correlates. HSCs were reported in 77% (66% weighted mean) of patients with memory disorders and 48% (47% weighted mean) of controls, and the prevalence increased with age in healthy subjects (r = 0.64, p = 0.047). A number of studies reported hypertension as a risk factor, and related their presence to poorer memory function. Further work is needed to fully understand the clinical significance of these lesions.

Introduction: The sensitive detection of mild cognitive impairment (MCI) in older adults is an important problem that requires objective assessment. We evaluated whether the computerised cognitive test battery, CogState, was as sensitive to MCI as two well-validated 'paper-and-pencil' tests, the Hopkins Verbal Learning Test (HVLT) and the Mini-Mental Status Examination (MMSE). Methods: These tests were administered with a subjective memory questionnaire and an 'Activities of Daily Living' scale to 21 individuals with MCI and 98 cognitively healthy controls matched for sex, education and IQ levels. The sensitivity and specificity of the tests and their discrimination between groups were determined. Results: The HVLT had a maximum discrimination between controls and MCI cases of 90%, compared with 86% for CogState and 65% for the MMSE. Only CogState showed correlations with subjective memory complaints (SMC) and activities of daily living for the whole cohort when controlled for age, sex and years of education. Logistic regression analyses showed that diagnosis (control:MCI) was predicted by HVLT and a CogState ratio score. Age was a significant predictor of HVLT performance, while age and SMC predicted CogState performance. The computerised test battery was well tolerated by older adults, but presentation speed was a limiting factor for some participants. Conclusions: Overall, we conclude that the HVLT has better sensitivity for the detection of MCI in older adults than the CogState, but that CogState may enable the identification of cognitive deficits above and beyond impairments in memory.

This methods paper outlines the overall design of a community-based multidisciplinary longitudinal study with the intent to stimulate interest and communication from scientists and practitioners studying the role of physical activity in preventive medicine. In adults, lack of regular exercise is a major risk factor in the development of chronic degenerative diseases and is a major contributor to obesity, and now we have evidence that many of our children are not sufficiently active to prevent early symptoms of chronic disease. The lifestyle of our kids (LOOK) study investigates how early physical activity contributes to health and development, utilizing a longitudinal design and a cohort of eight hundred and thirty 7-8-year-old (grade 2) school children followed to age 11-12 years (grade 6), their average family income being very close to that of Australia. We will test two hypotheses, that (a) the quantity and quality of physical activity undertaken by primary school children will influence their psychological and physical health and development; (b) compared with existing practices in primary schools, a physical education program administered by visiting specialists will enhance health and development, and lead to a more positive perception of physical activity. To test the first hypothesis we will monitor all children longitudinally over the 4 years. To test the second we will involve an intervention group of 430 children who receive two 50 min physical education classes every week from visiting specialists and a control group of 400 who continue with their usual primary school physical education with their class-room teachers. At the end of grades 2, 4, and 6 we will measure several areas of health and development including blood risk factors for chronic disease, cardiovascular structure and function, physical fitness, psychological characteristics and perceptions of physical activity, bone structure and strength, motor control, body composition, nutritional int

We hypothesized that carotid-femoral pulse wave velocity (PWV), a marker of arterial stiffness, interacts with age such that the magnitude of associations between PWV and cognitive performance are greater with increasing age and that this interaction is observed despite adjustments for demographic variables, mean arterial pressure, and cardiovascular risk factors. PWV was estimated using applanation tonometry in 409 dementia- and stroke-free participants of the Maine-Syracuse Longitudinal Study (24 to 92 years of age; 62.3% women). Using linear regression analyses in a cross-sectional design, associations between PWV and age and the interaction of PWV and age were examined in relation to a global composite score, the Wechsler Adult Intelligence Scale Similarities test (abstract reasoning), and 4 cognitive domains indexed by multiple cognitive measures. Adjusting for age, gender, education, height, weight, heart rate, mean arterial pressure, and antihypertensive treatment, PWV-by-age interactions were obtained for the global, visual-spatial organization and memory, scanning and tracking, and verbal episodic memory composites, as well as similarities. The combination of higher PWV and age resulted in progressively lower cognitive performance. This finding was the same with an extended model, which also included adjustment for cardiovascular risk factors and other confounds. PWV interacts with age in a multiplicative way to exert a negative influence on cognitive performance level. Early interventions to prevent an increase in arterial stiffness could possibly play an important role in the preservation of cognitive ability. (Hypertension. 2009;53:668-673.)

Childhood obesity is increasingly prevalent in the community and is related to adverse cardiovascular outcomes during adulthood. In this study of healthy children, we evaluated the influence of adiposity and physical activity on carotid-femoral pulse wave velocity (PWV), an index of arterial stiffness and a marker of cardiovascular risk in adults. In 573 community-based children (mean age: 10.1±0.3 years; 51% boys), we measured body mass index and waist circumference. Percentage body fat was quantitated by dual-energy x-ray absorptiometry. Cardiorespiratory fitness (CRF) and physical activity levels were assessed using a 20-m shuttle run and 7-day pedometer count, respectively. PWV was estimated by applanation tonometry. In univariate analysis, PWV was positively correlated with body mass index (r=0.34), waist circumference (r=0.32), and percentage body fat (r=0.32; P<0.001 for all) and negatively correlated with CRF (r= -0.23; P<0.001) and pedometer count (r= -0.08; P=0.046). In separate multivariable linear regression models, body mass index, waist circumference, and percentage of body fat were independently and positively associated with PWV (P<0.01 for all) after adjusting for age, sex, systolic blood pressure, mean arterial pressure, heart rate, and CRF (P<0.01 for all). The influence of CRF on PWV was attenuated after adjusting for adiposity. In conclusion, increased body mass and adiposity and decreased CRF are associated with arterial stiffening in healthy prepubescent children. (Hypertension. 2009;53:611-616.)

Background: Various charts based on body mass index (BMI) and per cent body fat (%BF) are used to classify childhood body composition but outcomes may vary. Aim: The study investigated variation in incidences of childhood obesity as depicted by four classification charts. Subjects and methods: BMI and DXA-derived %BF were assessed in 741 children. Incidences of overweight and obesity were compared between two BMI charts and two bioelectrical impedance (BIA)-based %BF charts. Results: The International Obesity Task Force (IOTF)-adopted BMI chart designated 21%, 6% (boys), and 26%, 9% (girls) as overweight and obese, respectively. Corresponding figures using the USA CDC BMI chart were 27%, 11% (boys) and 27%, 12% (girls). Using a USA-derived %BF chart incidences were 17%, 2% (boys) and 21%, 8% (girls) and using a UK-derived %BF chart 51%, 24% (boys) and 53%, 36% (girls). Sensitivity of BMI varied according to the %BF reference chart. Conclusions: In contrast to the BMI-based charts, there were considerable variations in depicted incidences of obesity between the %BF-based charts. These discordances were considered to result from previously reported variation within and between BIA and DXA %BF assessments underlying the charts. The present study highlights the need for valid, reliable, unchanging BIA and DXA procedures.

OBJECTIVES:: To investigate the relationship between markers of vitamin B12 status and brain volume loss per year over a 5-year period in an elderly population. METHODS:: A prospective study of 107 community-dwelling volunteers aged 61 to 87 years without

OBJECTIVE: An age-dependent relationship between aortic and left ventricular (LV) stiffening has been observed in community-based adults. Our aim was to compare the performances of wave reflection-dependent (pulse pressure) and independent [carotid-femoral pulse wave velocity (PWV)] indexes of aortic stiffness to detect preclinical LV diastolic dysfunction. METHODS: In this case-control study, a stratified subsample of participants of a population-based echocardiographic survey with LV ejection fraction higher than 45% and without overt heart failure was randomly selected to undergo assessment of brachial blood pressure, LV diastolic function by Doppler echocardiography, and estimation of central aortic pressures and PWV by applanation tonometry. RESULTS: Of the 233 subjects (mean age 73 ± 6 years, 54% men), 84 had normal diastolic function, 99 had mild diastolic dysfunction, and 50 had moderate or severe diastolic dysfunction. Brachial pulse pressure, central pulse pressure, and PWV progressively increased according to the severity of diastolic dysfunction, independent of age and sex. The overall performance of PWV was superior to brachial pulse pressure [area under receiver operating characteristic curve (AUC): 0.70 versus 0.59, respectively; P = 0.005] and central pulse pressure (AUC: 0.70 versus 0.56, respectively; P = 0.001) for the detection of any diastolic dysfunction. CONCLUSION: PWV appeared to be superior to central and brachial pulse pressure for the detection of diastolic dysfunction in older adults with 'preserved' LV ejection fraction.

Background: Previous studies have demonstrated a relationship between central adiposity and cognitive function. However, only some of these studies have adjusted for cardiovascular risk factors and cardiovascular disease, and none have also adjusted for physical activity level. Purpose: The purpose of the study was to examine the association between anthropometric measures of central adiposity (waist circumference and waist/hip ratio) and cognitive functioning with adjustment for cardiovascular disease risk factors and physical activity. Methods: Participants were 917 stroke- and dementia-free community-dwelling adults (59% women) in the Maine-Syracuse Study. The design was cross-sectional. Outcome measures included tests from the Wechsler Adult Intelligence Scale, the Halstead-Reitan Neuropsychological Battery, the Wechsler Memory Scale Revised, and the Mini-Mental State Examination. Results: Waist circumference and waist/hip ratio were inversely related to multiple cognitive domains with adjustment for age, education, gender, and number of prior exams. For example, a 20-cm increment in waist circumference was associated with a 0.14 SD decrement in the Global Composite score. These relations were attenuated with adjustment for cardiovascular disease risk factors. However, with further adjustment for physical activity level, only waist circumference remained significantly associated with performance on the Similarities test. Conclusions: Waist circumference and waist/hip ratio are inversely related to cognitive function. Measures of central adiposity predict cognitive function independently of associated cardiovascular risk factors and events; however, the association between central adiposity and cognitive function is attenuated, to a large extent, by adjustment for physical activity level. Physical activity is an important covariate in studies relating measures of central adiposity to cognition.