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2.  Atrial fibrillation is associated with reduced brain volume and cognitive function independent of cerebral infarcts 
Background and Purpose
Atrial fibrillation (AF) has been associated with cognitive decline independant of stroke, suggesting additional effects of AF on the brain. We aimed to assess the association between AF and brain function and structure in a general elderly population.
Methods
This is a cross-sectional analysis on 4251 non-demented participants (mean age 76 ± 5 years) in the population-based AGES-Reykjavik Study. Medical record data were collected on the presence, subtype and time from first diagnosis of AF; 330 participants had AF. Brain volume measurements, adjusted for intracranial volume, and presence of cerebral infarcts were determined with MRI. Memory, speed of processing and executive function composites were calculated from a cognitive test battery. In a multivariable linear regression model, adjustments were made for demographic, cardiovascular risk factors and cerebral infarcts.
Results
Participants with AF had lower total brain volume compared to those without AF (p<0.001). The association was stronger with persistent/permanent than paroxysmal AF and with increased time from the first diagnosis of the disease. Of the brain tissue volumes, AF was associated with lower volume of gray and white matter (p<0.001 and p=0.008 respectively) but not of white matter hyperintesities (p=0.49). Participants with AF scored lower on tests on memory.
Conclusions
AF is associated with smaller brain volume and the association is stronger with increasing burden of the arrhythmia. These findings suggest that AF has a cumulative negative effect on the brain independent of cerebral infarcts.
doi:10.1161/STROKEAHA.12.679381
PMCID: PMC3632359  PMID: 23444303
atrial fibrillation; brain imaging; cognition; cerebral infarct
3.  Objective measurements of daily physical activity patterns and sedentary behaviour in older adults: Age, Gene/Environment Susceptibility-Reykjavik Study 
Age and Ageing  2012;42(2):222-229.
Background: objectively measured population physical activity (PA) data from older persons is lacking. The aim of this study was to describe free-living PA patterns and sedentary behaviours in Icelandic older men and women using accelerometer.
Methods: from April 2009 to June 2010, 579 AGESII-study participants aged 73–98 years wore an accelerometer (Actigraph GT3X) at the right hip for one complete week in the free-living settings.
Results: in all subjects, sedentary time was the largest component of the total wear time, 75%, followed by low-light PA, 21%. Moderate-vigorous PA (MVPA) was <1%. Men had slightly higher average total PA (counts × day−1) than women. The women spent more time in low-light PA but less time in sedentary PA and MVPA compared with men (P < 0.001). In persons <75 years of age, 60% of men and 34% of women had at least one bout ≥10 min of MVPA, which decreased with age, with only 25% of men and 9% of women 85 years and older reaching this.
Conclusion: sedentary time is high in this Icelandic cohort, which has high life-expectancy and is living north of 60° northern latitude.
doi:10.1093/ageing/afs160
PMCID: PMC3575120  PMID: 23117467
physical activity; accelerometry; sedentary behaviour; older adults; BMI; AGES-Reykjavik; older people
4.  Cardiovascular Health through Young Adulthood and Cognitive Functioning in Midlife 
Annals of neurology  2013;73(2):170-179.
Objective
To examine the association between overall cardiovascular health as recently defined by the American Heart Association in young adulthood to middle-age and cognitive function in midlife. Overall ideal cardiovascular health incorporates 7 metrics, including the avoidance of overweight or obesity, a healthful diet, nonsmoking, and physical activity, total cholesterol, blood pressure, and fasting glucose at goal levels.
Methods
This analysis of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter community-based study with 25 years of follow-up, included 2,932 participants aged 18 to 30 years at baseline (Year 0) who attended follow-up exams at Years 7 and 25. Cardiovascular health metrics were measured at each examination. The Digit Symbol Substitution Test (DSST), modified Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT) were completed at Year 25.
Results
A greater number of ideal cardiovascular metrics in young adulthood and middle-age was independently associated with better cognitive function in midlife (p-trend<0.01, for all). Specifically, each additional ideal metric was associated with 1.32 more symbols on the DSST (95% CI: 0.93 to 1.71), a 0.77-point lower interference score on the Stroop Test (−1.03 to −0.45), and 0.12 more words on the RAVLT (0.04 to 0.20). Participants who had ≥5 ideal metrics at a greater number of the 3 examinations over the 25-year period exhibited better performance on each cognitive test in middle-age (p-trend<0.01, for all).
Interpretation
Ideal cardiovascular health in young adulthood and its maintenance to middle-age is associated with better psychomotor speed, executive function, and verbal memory in midlife.
doi:10.1002/ana.23836
PMCID: PMC3608821  PMID: 23443990
5.  Adverse Oral Health and Cognitive Decline: The Health, Aging and Body Composition Study 
Background/Objectives
Periodontal disease has been associated with poorer cross-sectional cognitive function and is correlated with adverse vascular outcomes, but has received little prospective investigation in relation to cognitive decline.
Design
Analysis of a prospective cohort study.
Setting
The Health, Aging and Body Composition (Health ABC) Study
Participants and measurements
We examined the prospective association between a range of oral health parameters and cognitive function using data on 1053 participants who were administered the Modified Mini-Mental State Examination (3MS) at year 1 (baseline) and year 3, and had participated in a comprehensive periodontal examination at year 2. We investigated 3MS decline from year 3 to 5 in 947 (89.9%) participants. Covariates included age, sex, education, race, cardiovascular disease/risk and depressive symptoms.
Results
Most indicators of adverse oral health at year 2 were associated with cognitive impairment based on averaged 3MS scores <80 for years 1 and 3, but these associations were substantially confounded by education and race. Higher gingival index, a measure of gingival inflammation, at year 2 remained independently associated with this definition of cognitive impairment and, in fully adjusted analyses, was also an independent predictor of a 5+ point cognitive decline from years 3 to 5.
Conclusion
Periodontitis may be a risk factor for cognitive decline. Gingivitis is reversible and periodontitis to some degree is preventable and controllable when manifest. Therefore, further research is needed to clarify potential underlying mechanisms and oral health interventions that potentially might ameliorate cognitive decline.
doi:10.1111/jgs.12094
PMCID: PMC3578234  PMID: 23405916
cognitive decline; cognitive impairment; periodontitis; periodontal diseases; gingivitis
6.  Pulmonary Function Impairment May be An Early Risk Factor for Late-Life Cognitive Impairment 
Background
Low pulmonary function (PF) is associated with poor cognitive function and dementia. There are few studies of change in PF in mid-life and late-life cognitive status.
Design and Participants
We studied this is 3,665 subjects from AGES-Reykjavik Study who had at least one measure of forced expiratory volume/ 1 sec (FEV1) and were cognitively tested on average 23 years later. A subset of 1,281 subjects had two or three measures of FEV1 acquired over a 7.8 year period. PF was estimated as FEV1/Height2. Rate of PF decline was estimated as the slope of decline over time. Cognitive status was measured with continuous scores of memory, speed of processing, and executive function, and as the dichotomous outcomes of mild cognitive impairment (MCI) and dementia.
Results
Lower PF measured in mid-life predicted lower memory, speed of processing, executive function, and higher likelihood of MCI and dementia 23 years later. Decrease of PF over a 7.8-year period in mid-life was not associated with lower cognitive function or dementia.
Conclusion
Reduced PF measured in mid-life may be an early marker of later cognitive problems. Additional studies characterizing early and late PF changes are needed.
doi:10.1111/jgs.12069
PMCID: PMC3545414  PMID: 23311554
Cognition; Dementia; Forced Expiratory Volume; Longitudinal Cohort Studies
7.  Cerebral microbleeds and age-related macular degeneration: The AGES-Reykjavik Study 
Neurobiology of aging  2012;33(12):2935-2937.
We test the hypothesis that cerebral microbleeds (CMB) and age-related macular degeneration (AMD), both linked to amyloid-β deposition, are correlated. This study includes 4205 participants (mean age 76.2; 57.8% women) in the AGES-Reykjavik Study (2002–2006). CMB were assessed from magnetic resonance images and AMD from digital retinal images. Data were analyzed with multinomial logistic models controlling for major confounders. Evidence of CMB was detected in 476 persons (272 with strict lobar CMB and 204 with non-lobar CMB). AMD was detected in 1098 persons (869 with early AMD, 140 with exudative AMD, and 89 with pure geographic atrophy). Early and exudative AMD were not associated with CMB. The adjusted odds ratio of pure geographic atrophy was 1.62 (95% confidence interval 0.93–2.82, P=0.089) for having any CMB, 1.43 (0.66–3.06, P=0.363) for strict lobar CMB, and 1.85 (0.89–3.87, P=0.100) for non-lobar CMB. This study provides no evidence that amyloid deposits in the brain and AMD are correlated. However, the suggestive association of geographic atrophy with CMB warrants further investigation.
doi:10.1016/j.neurobiolaging.2012.01.012
PMCID: PMC3368038  PMID: 22382405
Age-related macular degeneration; Cerebral microbleeds; Amyloid-β; The AGES-Reykjavik Study
8.  AGE EFFECTS ON HIPPOCAMPAL STRUCTURAL CHANGES IN OLD MEN: THE HAAS 
NeuroImage  2007;40(3):1003-1015.
Understanding the variability of the hippocampus in human brain research is essential. The effect of age on the hippocampus has been explored in several studies that have been focused on either normal aging or neural degeneration. Shape analysis of magnetic resonance imaging (MRI) provides morphological measures for brain structures. This study further investigates the age effects on hippocampal morphology in three groups (104 normal controls, 24 Alzheimer’s disease (AD) and 14 vascular dementia (VaD) patients). By utilizing a parametric shape analysis of hippocampal MRI scans, each individual distance map is generated and analyzed statistically. Specifically, after eliminating similarity parameters (rotation, translation, and scaling) effects for each hippocampus, an individual distance map is generated from parametric hippocampal surfaces and medial axes. Then statistical methods, including regression, and permutation tests, are applied to detect the differences in hippocampal distance maps and volumes under the effect of age in each group. Statistical analyses reveal that the loss of hippocampal volume and changes in shape are more significantly related to aging in the control group than in AD/VaD. The results also show that the asymmetry of hippocampus in healthy subjects is greater than that in either of the disease groups. Our study shows that 3D statistical shape analysis could enhance the understanding of age effects on local areas of hippocampi. However, the sample sizes of disease groups are relatively low; further studies with more AD/VaD data are needed.
doi:10.1016/j.neuroimage.2007.12.034
PMCID: PMC3785795  PMID: 18280181
Statistical shape analysis; age; hippocampus; Alzheimer’s disease; vascular dementia
9.  Vascular Contributions to Cognitive Impairment and Dementia 
Background and Purpose
This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.
Methods
Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.
Results
The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.
Conclusions
Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.
doi:10.1161/STR.0b013e3182299496
PMCID: PMC3778669  PMID: 21778438
AHA Scientific Statements; vascular dementia; Alzheimer disease; risk factors; prevention; treatment
10.  Low blood pressure, antihypertensive treatment, and physical and mental health status in patients with arterial disease. The SMART-Study 
Journal of internal medicine  2013;274(3):241-251.
Objective
To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease.
Design
Cross-sectional analyses within the Secondary Manifestations of ARTerial disease (SMART) study, a single centre cohort study.
Setting
Hospitalized care.
Subjects
5,877 patients (mean age 57) with symptomatic and asymptomatic arterial disease who underwent a standardized vascular screening.
Main outcome measure
Self-rated physical and mental health assessed with the Short Form (SF)-36.
Results
In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment was associated with poorer health status independent of important confounders including BP levels; adjusted mean differences (95%CI) in physical and mental health between 0 and ≥3 antihypertensives were -1.2 (-2.1, -0.3) and -3.5 (-4.4; -2.6). Furthermore, lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independently of antihypertensive treatment. Mean differences (95%CI) in physical and mental health status per SD decrease in systolic BP were -0.56 (-0.84; -0.27) and -0.32 (-0.61; -0.03), and per SD decrease in diastolic BP -0.50 (-0.78; -0.23) and -0.08 (-0.36; 0.20). The association between low BP and poor health status was particularly present in patients with coronary artery disease.
Conclusions
In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These results might indicate that there are different underlying mechanisms explaining these independent associations.
doi:10.1111/joim.12069
PMCID: PMC3750200  PMID: 23527863
antihypertensive treatment; blood pressure; physical health; mental health; cardiovascular disease
11.  Coronary artery calcium distributions in older persons in the AGES-Reykjavik study 
European journal of epidemiology  2012;27(9):673-687.
Coronary Artery Calcium (CAC) is a sign of advanced atherosclerosis and an independent risk factor for cardiac events. Here, we describe CAC-distributions in an unselected aged population and compare modelling methods to characterize CAC-distribution. CAC is difficult to model because it has a skewed and zero inflated distribution with over-dispersion. Data are from the AGES-Reykjavik sample, a large population based study [2002-2006] in Iceland of 5,764 persons aged 66-96 years.
Linear regressions using logarithmic- and Box-Cox transformations on CAC+1, quantile regression and a Zero-Inflated Negative Binomial model (ZINB) were applied. Methods were compared visually and with the PRESS-statistic, R2 and number of detected associations with concurrently measured variables.
There were pronounced differences in CAC according to sex, age, history of coronary events and presence of plaque in the carotid artery. Associations with conventional coronary artery disease (CAD) risk factors varied between the sexes.
The ZINB model provided the best results with respect to the PRESS-statistic, R2, and predicted proportion of zero scores. The ZINB model detected similar numbers of associations as the linear regression on ln(CAC+1) and usually with the same risk factors.
doi:10.1007/s10654-012-9730-6
PMCID: PMC3746182  PMID: 22990371
Coronary artery calcium; epidemiology; older persons; skewed distribution; ZINB; statistical modelling
12.  Effect of vertebral fractures on function, quality of life and hospitalisation the AGES-Reykjavik study 
Age and Ageing  2012;41(3):351-357.
Background: understanding the determinants of health burden after a fracture in ageing populations is important.
Objective: assess the effect of clinical vertebral and other osteoporotic fractures on function and the subsequent risk of hospitalisation.
Design: individuals from the prospective population-based cohort study Age, Gene/Environment Susceptibility (AGES)-Reykjavik study were examined between 2002 and 2006 and followed up for 5.4 years.
Subjects: a total of 5,764 individuals, 57.7% women, born 1907–35, mean age 77.
Method: four groups with a verified fracture status were used; vertebral fractures, other osteoporotic fractures excluding vertebral, non-osteoporotic fractures and not-fractured were compared and analysed for the effect on mobility, strength, QoL, ADL, co-morbidity and hospitalisation.
Results: worst performance on functional tests was in the vertebral fracture group for women (P < 0.0001) and the other osteoporotic fractures group for men (P < 0.05). Both vertebral and other osteoporotic fractures, showed an increased risk of hospitalisation, HR = 1.4 (95% CI: 1.3–1.7) and 1.2 (95% CI: 1.1–1.2) respectively (P < 0.0001). Individuals with vertebral fractures had 50% (P < 0.0001) longer hospitalisation than not-fractured and 33% (P < 0.002) longer than the other osteoporotic fractures group.
Conclusion: individuals with a history of clinical vertebral fracture seem to carry the greatest health burden compared with other fracture groups, emphasising the attention which should be given to those individuals.
doi:10.1093/ageing/afs003
PMCID: PMC3335370  PMID: 22367357
vertebral fracture; health burden; osteoporotic fracture; strength; ADL; quality of life; mobility; elderly
13.  Structural Brain Changes in Migraine 
Context
A previous cross-sectional study showed an association of migraine with a higher prevalence of magnetic resonance imaging (MRI)–measured ischemic lesions in the brain.
Objective
To determine whether women or men with migraine (with and without aura) have a higher incidence of brain lesions 9 years after initial MRI, whether migraine frequency was associated with progression of brain lesions, and whether progression of brain lesions was associated with cognitive decline.
Design, Setting, and Participants
In a follow-up of the 2000 Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis cohort, a prospective populationbased observational study of Dutch participants with migraine and an age- and sexmatched control group, 203 of the 295 baseline participants in the migraine group and 83 of 140 in the control group underwent MRI scan in 2009 to identify progression of MRI-measured brain lesions. Comparisons were adjusted for age, sex, hypertension, diabetes, and educational level. The participants in the migraine group were a mean 57 years (range, 43–72 years), and 71% were women. Those in the control group were a mean 55 years (range, 44–71 years), and 69% were women.
Main Outcome Measures
Progression of MRI-measured cerebral deep white matter hyperintensities, infratentorial hyperintensities, and posterior circulation territory infarctlike lesions. Change in cognition was also measured.
Results
Of the 145 women in the migraine group, 112 (77%) vs 33 of 55 women (60%) in the control group had progression of deep white matter hyperintensities (adjusted odds ratio [OR], 2.1; 95%CI, 1.0–4.1; P=.04). There were no significant associations of migraine with progression of infratentorial hyperintensities: 21 participants (15%) in themigraine group and 1 of 57 participants (2%) in the control group showed progression (adjusted OR, 7.7; 95% CI, 1.0–59.5; P=.05) or new posterior circulation territory infarctlike lesions: 10 of 203 participants (5%) in the migraine group but none of 83 in the control group (P=.07). There was no association of number or frequency of migraine headaches with progression of lesions. There was no significant association of high vs nonhigh deep white matter hyperintensity load with change in cognitive scores ( 3.7 in the migraine group vs 1.4 in the control group; 95% CI, 4.4 to 0.2; adjusted P=.07).
Conclusions
In a community-based cohort followed up after 9 years, women with migraine had a higher incidence of deep white matter hyperintensities but did not have significantly higher progression of other MRI-measured brain changes. There was no association of migraine with progression of any MRI-measured brain lesions in men.
doi:10.1001/jama.2012.14276
PMCID: PMC3633206  PMID: 23150008
14.  Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons 
Neurobiology of Aging  2011;33(4):827.e11-827.e19.
Epidemiological studies suggest that elevated blood pressure (BP) in mid-life is associated with increased risk of Alzheimer’s disease (AD) in late-life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid-beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late-middle-aged to older adult apolipoprotein E (APOE) ε4 homozygotes, heterozygotes and non-carriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB DVRs and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower CMRgl in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late-mid-life may be associated with increased risk of presymptomatic AD.
doi:10.1016/j.neurobiolaging.2011.06.020
PMCID: PMC3236809  PMID: 21821316
APOE; blood pressure; arterial stiffness; brain imaging; PET; Alzheimer’s disease; amyloid; PiB; Pittsburgh Compound-B
15.  Poor Cognitive Function and Risk of Severe Hypoglycemia in Type 2 Diabetes 
Diabetes Care  2012;35(4):787-793.
OBJECTIVE
Self-management of type 2 diabetes including avoidance of hypoglycemia is complex, but the impact of cognition on safe self-management is not well understood. This study aimed to assess the effect of baseline cognitive function and cognitive decline on subsequent risk of severe hypoglycemia and to assess the effect of different glycemic strategies on these relationships.
RESEARCH DESIGN AND METHODS
Prospective cohort analysis of data from the ACCORD trial included 2,956 adults aged ≥55 years with type 2 diabetes and additional cardiovascular risk factors. Cognitive tests (Digit Symbol Substitution Test [DSST], Rey Auditory Verbal Learning Test, Stroop Test, and Mini Mental Status Examination) were conducted at baseline and 20 months. Study outcomes were incident confirmed severe hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any assistance (HAA).
RESULTS
After a median 3.25-year follow-up, a 5-point-poorer baseline score on the DSST was predictive of a first episode of HMA (hazard ratio 1.13 [95% CI 1.08–1.18]). Analyses of the other cognitive tests and of HAA were consistent with the DSST results. Cognitive decline over 20 months increased the risk of subsequent hypoglycemia to a greater extent in those with lower baseline cognitive function (Pinteraction = 0.037). Randomization to an intensive versus standard glycemic strategy had no impact on the relationship between cognitive function and the risk of severe hypoglycemia.
CONCLUSIONS
Poor cognitive function increases the risk of severe hypoglycemia in patients with type 2 diabetes. Clinicians should consider cognitive function in assessing and guiding their patients regarding safe diabetes self-management regardless of their glycemic targets.
doi:10.2337/dc11-1855
PMCID: PMC3308284  PMID: 22374637
16.  Midlife blood pressure, plasma β amyloid and the risk for Alzheimer’s disease: the Honolulu Asia Aging Study 
Hypertension  2012;59(4):780-786.
Beta-amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer’s disease (AD) and possibly vascular dementia (VaD). We investigated the joint association of mid-life BP and Aβ peptide levels with the risk for late-life AD and VaD. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965 – 2000). Mid-life BP was measured starting in 1971 participants mean age 58 years, Aβ was measured in specimens collected1980/82, and assessment of dementia and autopsy collection started in 1991/93. The outcome measures were prevalent (present in 1991/3) and incident AD (n= 53, including 38 with no contributing cardiovascular disease), and VaD (n=24). Cerebral amyloid angiopathy (CAA), β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in post-mortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.4 – 3.1; Aβ1-42 HR 1.6, 95% CI 1.1 – 2.3). Evidence of interaction between diastolic BP and plasma Aβ (1-40 pinteraction <0.05; 1-42 pinteraction <0.07) levels, indicated the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of CAA (ptrend<0.05), but not the other neuropathologies. Aβ plasma levels start decreasing at least 15 years before AD is diagnosed, and the association of Aβ to AD is modulated by mid-life diastolic BP. Elevated BP may compromise vascular integrity leading to CAA and impaired Aβ clearance from the brain.
doi:10.1161/HYPERTENSIONAHA.111.178962
PMCID: PMC3319436  PMID: 22392902
Amyloid; blood pressure; brain; aging; dementia
17.  The Promises and Pitfalls of Genoeconomics* 
Annual review of economics  2012;4:627-662.
This article reviews existing research at the intersection of genetics and economics, presents some new findings that illustrate the state of genoeconomics research, and surveys the prospects of this emerging field. Twin studies suggest that economic outcomes and preferences, once corrected for measurement error, appear to be about as heritable as many medical conditions and personality traits. Consistent with this pattern, we present new evidence on the heritability of permanent income and wealth. Turning to genetic association studies, we survey the main ways that the direct measurement of genetic variation across individuals is likely to contribute to economics, and we outline the challenges that have slowed progress in making these contributions. The most urgent problem facing researchers in this field is that most existing efforts to find associations between genetic variation and economic behavior are based on samples that are too small to ensure adequate statistical power. This has led to many false positives in the literature. We suggest a number of possible strategies to improve and remedy this problem: (a) pooling data sets, (b) using statistical techniques that exploit the greater information content of many genes considered jointly, and (c) focusing on economically relevant traits that are most proximate to known biological mechanisms.
doi:10.1146/annurev-economics-080511-110939
PMCID: PMC3592970  PMID: 23482589
genetics; heritability; GWAS
18.  Lifestyle and the Risk of Dementia Among Japanese American Men 
Objectives
To determine whether adhering to a healthy lifestyle in midlife may reduce the risk of dementia.
Design
Case-control study nested in a prospective cohort.
Setting
The Honolulu-Asia Aging Study on Oahu, Hawaii.
Participants
3468 Japanese American men (mean age 52, 1965–1968) examined for dementia after 25 years.
Measurements
Men at low risk were defined as those with the following midlife characteristics: nonsmoking, body mass index <25.0 kg/m2, physically active, and having a healthy diet (based on alcohol, dairy, meat, fish, fruit, vegetables, cereals, and monounsaturated-to-saturated fat). Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for developing overall dementia, Alzheimer’s disease (AD), and vascular dementia (VaD), adjusting for potential confounders.
Results
Dementia was diagnosed in 6.4% of men (52.5% with AD, 35.0% with VaD). Examining the risk factors individually, BMI was most strongly associated with increased risk of overall dementia (OR, 1.87; 95% CI, 1.26–2.77; BMI >25.0 vs. <22.6 kg/m2). All of the individual risk factors except diet score were significantly associated with VaD, whereas none were significantly associated with AD alone. Men with all four low-risk characteristics (7.2% of cohort) had the lowest OR for overall dementia (OR, 0.36; 95% CI, 0.15–0.84), as compared to other men. There were no significant associations between the combined low-risk characteristics and the risk of AD alone.
Conclusion
Having a healthy lifestyle in midlife is associated with a lower risk of dementia in late life among Japanese American men.
doi:10.1111/j.1532-5415.2011.03768.x
PMCID: PMC3258374  PMID: 22211390
dementia; lifestyle; risk
19.  Arterial Stiffness and Cognitive Decline in Well-Functioning Older Adults 
Background.
Stiffness of the central arteries in aging may contribute to cerebral microvascular disease independent of hypertension and other vascular risk factors. Few studies of older adults have evaluated the association of central arterial stiffness with longitudinal cognitive decline.
Methods.
We evaluated associations of aortic pulse wave velocity (centimeters per second), a measure of central arterial stiffness, with cognitive function and decline in 552 participants in the Health, Aging, and Body Composition (Health ABC) study Cognitive Vitality Substudy (mean age ± SD = 73.1 ± 2.7 years, 48% men and 42% black). Aortic pulse wave velocity was assessed at baseline via Doppler-recorded carotid and femoral pulse waveforms. Global cognitive function, verbal memory, psychomotor, and perceptual speed were evaluated over 6 years.
Results.
After adjustment for demographics, vascular risk factors, and chronic conditions, each 1 SD higher aortic pulse wave velocity (389 cm/s) was associated with poorer cognitive function: −0.11 SD for global function (SE = 0.04, p < .01), −0.09 SD for psychomotor speed (SE = 0.04, p = .03), and −0.12 SD for perceptual speed (SE = 0.04, p < .01). Higher aortic pulse wave velocity was also associated with greater decline in psychomotor speed, defined as greater than 1 SD more than the mean change (odds ratio = 1.42 [95% confidence interval = 1.06, 1.90]) but not with verbal memory or longitudinal decline in global function, verbal memory, or perceptual speed. Results were consistent with mixed models of decline in each cognitive test.
Conclusions.
In well-functioning older adults, central arterial stiffness may contribute to cognitive decline independent of hypertension and other vascular risk factors.
doi:10.1093/gerona/glr119
PMCID: PMC3210954  PMID: 21768503
Aging; Arterial stiffness; Cognitive decline
20.  Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility – Reykjavik Study 
Brain  2011;134(11):3398-3407.
Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid–femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility – Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69–93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta–carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta–carotid reflection coefficient (R = −0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid–femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62–1.71 per standard deviation, P<0.002). Carotid–femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (−0.127 ± 0.037 SD/SD, P<0.001), grey matter (−0.079 ± 0.038 SD/SD, P = 0.038) and white matter (−0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid–femoral pulse wave velocity (−0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (−0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (−0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (−0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (−0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.
doi:10.1093/brain/awr253
PMCID: PMC3212721  PMID: 22075523
haemodynamics; aortic stiffness; magnetic resonance imaging; brain structure; cognitive function
21.  Microinfarcts, brain atrophy, and cognitive function: the HAAS autopsy study 
Annals of neurology  2011;70(5):774-780.
Objectives
To study the association of microinfarcts (MBI) to ante-mortem global cognitive function (CF), and to investigate whether brain weight (BW), Alzheimer’s lesions (neurofibrillary tangles (NFT) or neuritic plaques (NP) mediate the association.
Methods
Subjects are 437 well-characterized male decedents from the Honolulu Asia Aging Autopsy Study. Brain pathology was ascertained with standardized methods, CF was measured by the Cognitive Abilities Screening Instrument (CASI)and data were analyzed using formal mediation analyses, adjusted for age at death, time between last CF measure and death, education, and head size. Based on ante-mortem diagnoses, demented and non-demented subjects were examined together and separately.
Results
In those with no dementia, MBI were strongly associated with the last ante-mortem CF score; this was significantly mediated by BW, and not NFT or NP. In contrast, among those with an ante-mortem diagnosis of dementia, NFT had the strongest associations with BW and with CF, and MIB were modestly associated with CF.
Interpretation
This suggests microinfarct pathology is a significant and independent factor contributing to brain atrophy and cognitive impairment, particularly before dementia is clinically evident. The role of vascular damage as initiator, stimulator, or additive contributor to neurodegeneration may differ depending on when in the trajectory towards dementia the lesions develop.
doi:10.1002/ana.22520
PMCID: PMC3241005  PMID: 22162060
22.  Effects of randomization to intensive glucose lowering on brain structure and function in type 2 diabetes ACCORD Memory in Diabetes Study 
Lancet Neurology  2011;10(11):969-977.
Background
Persons with type 2 diabetes (T2D) are at risk for cognitive impairment and brain atrophy. The ACCORD Memory in Diabetes (MIND) Study investigated whether persons randomized to an intensive glycaemic therapeutic strategy targeting HbA1c to <6% had better cognitive function and a larger brain volume at 40 months than persons randomized to a standard strategy targeting HbA1c to 7%–7.9%.
Methods
ACCORD MIND was a double 2×2 factorial parallel group randomised trial conducted in 52 clinical sites in North America. Participants [age 55 – <80 years] with T2D, high HbA1c concentrations (>7.5%), and at high risk for cardiovascular events were randomised to treatment groups using a centralized web-based system. Clinic staff and participants were not blinded to treatment arm. The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 participants. All participants with follow-up data were included in the primary analyses. In February, 2008, increased mortality risk led to the termination of the intensive therapy and transition of those participants to standard glycaemic treatment.
Results
Randomised patients (n=2977; mean age 62.3 years) were consecutively enrolled; the final analysis included 1358 intensive and 1416 standard arm participants with a 20 or 40 month DSST score. Of the 614 with a baseline MRI, 230 intensive and 273 standard therapy participants were included in the analysis. There was no treatment difference in the DSST score. The intensive group had a greater TBV than the standard group (difference, 4.62; 95% CI 2.0 to7.3 cm3; p=0.0007).
Interpretation
Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND participants. (ClinicalTrials.gov number, NCT00182910).
doi:10.1016/S1474-4422(11)70188-0
PMCID: PMC3333485  PMID: 21958949
23.  Heterogeneity in White Blood Cells Has Potential to Confound DNA Methylation Measurements 
PLoS ONE  2012;7(10):e46705.
Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50–179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4–15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.
doi:10.1371/journal.pone.0046705
PMCID: PMC3465258  PMID: 23071618
24.  AD brain pathology: Vascular origins? Results from the HAAS Autopsy Study 
Neurobiology of aging  2007;29(10):1587-1590.
An increasing number of studies suggest a vascular contribution to Alzheimer’s disease [AD]. One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration [amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles] were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment.
doi:10.1016/j.neurobiolaging.2007.03.008
PMCID: PMC3437222  PMID: 17466414
25.  Cerebral Microbleeds: A Field Guide to their Detection and Interpretation 
Lancet neurology  2009;8(2):165-174.
Summary
Cerebral microbleeds (CMB) are increasingly recognized neuroimaging findings, occurring with cerebrovascular disease, dementia, and normal aging. Recent years have seen substantial progress, particularly in developing newer MRI methodologies for CMB detection and applying them to population-based elderly samples. This review focuses on these recent developments and their impact on two major questions: how CMB are detected, and how they should be interpreted. There is now ample evidence that prevalence and number of detected CMB varies with MRI characteristics such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength, and post-processing, underlining the importance of MRI technique in interpreting studies. Recent investigations using sensitive techniques find the prevalence of CMB detected in community-dwelling elderly to be surprisingly high. We propose procedural guidelines for identifying CMB and suggest possible future approaches for elucidating the role of these common lesions as markers for, and potential contributors to, small vessel brain disease.
doi:10.1016/S1474-4422(09)70013-4
PMCID: PMC3414436  PMID: 19161908

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