Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: A longitudinal, population-based prospective cohort study.

BACKGROUND: Vascular risk factors have been proposed as important targets for the prevention of dementia. As lipid fractions represent easily modifiable targets, we examined the longitudinal relationship of baseline lipid fractions with 13-y incident dementia and its subtypes (Alzheimer disease [AD] and mixed or vascular dementia) in older community-dwelling persons. METHODS AND FINDINGS: Non-institutionalized persons aged 65+ y (n = 9,294) were recruited for the Three-City Study (3C Study), a population-based cohort study from the electoral rolls of the cities of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. Follow-up examinations were performed every 2 y after the baseline assessment. The final study sample comprised 7,470 participants from the 3C Study (mean age ± standard deviation [SD] 73.8 ± 5.3 y, 61.0% women) who were prospectively followed up for up to 13 y. Fasting lipid fractions (triglycerides [TGs], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC]) were studied as continuous variables, and results are reported per SD increase of each lipid fraction. Incident dementia and its subtypes were studied as censored variables using Cox models with age as time scale. Analyses were adjusted for sex, study center, and educational level, as well as vascular risk factors and apolipoprotein E (APOE) ε4 genotype. We corrected for multiple testing, yielding a significance threshold of 0.0169. p-Values above the significance threshold but less than 0.05 were considered nominally significant. During a mean (± SD) follow-up period of 7.9 ± 3.6 y, 779 participants developed incident dementia (n = 532 AD and n = 154 mixed or vascular dementia). Higher LDL-C and TC concentrations at baseline were associated with an increased risk of AD (hazard ratio [HR] per SD increase = 1.13 [95% CI 1.04-1.22], p = 0.0045, and HR = 1.12 [1.03-1.22], p = 0.0072, respectively). These associations were largely unchanged after adjustment for vascular risk factors and were attenuated after adjustment for APOEε4 (HR per SD increase = 1.12 [1.03-1.23], p = 0.0110, and HR = 1.12 [1.02-1.23], p = 0.0171, respectively). Higher TG concentrations at baseline were associated with an increased risk of all dementia (HR per SD increase = 1.11 [1.03-1.19], p = 0.0044) and mixed or vascular dementia (HR = 1.21 [1.04-1.41], p = 0.0163). However, these associations disappeared after adjusting for vascular risk factors (HR = 1.07 [0.98-1.17], p = 0.1374, and HR = 1.17 [0.96-1.42], p = 0.1206, respectively). Main limitations of the study include interval censoring of incident dementia cases, potential selective survival bias, and the fact that variation in lipid concentrations during follow-up could not be accounted for in the analyses. CONCLUSIONS: In a large population-based sample of older community-dwelling persons with up to 13 y of follow-up, we observed that higher LDL-C and TC concentrations were associated with an increased risk of AD. This result was independent of vascular risk factors and was attenuated after adjustment for APOEε4 carrier status. TG and HDL-C concentrations were not associated with risk of incident dementia or its subtypes after accounting for vascular risk factors.

Long-Term Clinical Impact of Vascular Brain Lesions on Magnetic Resonance Imaging in Older Adults in the Population.

BACKGROUND AND PURPOSE: White matter hyperintensity (WMH) volume and covert brain infarcts are highly prevalent in older adults and are often asymptomatic. We compared the impact of WMH volume and brain infarcts on risk of clinical stroke and dementia in older adults in the population. METHODS: Participants were 1677 individuals aged ≥65 years from the 3-City Dijon study, who were free of stroke and dementia at baseline, followed-up for ≤12 years. RESULTS: Both lesion types were comparably associated with an increased risk of stroke (adjusted hazard ratio, 1.72; 95% confidence interval, 1.24-2.40 for WMH volume and hazard ratio, 2.15; 95% confidence interval, 1.18-3.93 for brain infarcts), but only WMH volume was associated with an increased risk of dementia (hazard ratio, 1.41; 95% confidence interval, 1.09-1.83). CONCLUSIONS: The differential impact of WMH and brain infarcts on clinical stroke and dementia suggests relatively different prognostic value of the 2 lesions. WMHs may represent a particularly pertinent magnetic resonance imaging intermediate marker that can be utilized in optimizing prevention strategies for both stroke and dementia in primary care and in trials.

Differential Effect of White-Matter Lesions and Covert Brain Infarcts on the Risk of Ischemic Stroke and Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: We examined the association of white-matter hyperintensity (WMH) volume and covert brain infarcts, which are the 2 major magnetic resonance imaging markers of covert cerebrovascular disease in older adults, with long-term risk of ischemic stroke and intracerebral hemorrhage (ICH) in the general population. METHODS: Participants were 1731 individuals aged ≥65 years from the Three-City Dijon study. We studied the association of WMH volume and brain infarct, with incident ischemic stroke overall, and by subtype, and with incident ICH. RESULTS: High total, periventricular, and deep WMHs were associated with incident ICH. Extensive periventricular WMH volume was associated with increased risk of ischemic stroke (hazard ratio, 1.94; 95% confidence interval, 1.12-3.35), particularly cardioembolic stroke. Covert brain infarcts were associated with incident ICH but not with incident ischemic stroke or its subtypes. CONCLUSIONS: Although of ischemic nature, both WMH volume and covert brain infarcts portend a major risk of ICH. If confirmed in independent studies, these findings could have important implications for the clinical management of covert vascular brain lesions.

Midlife stroke risk and cognitive decline: a 10-year follow-up of the Whitehall II cohort study.

BACKGROUND: Stroke is associated with an increased risk of dementia. However, it is unclear whether risk of stroke in those free of stroke, particularly in nonelderly populations, leads to differential rates of cognitive decline. Our aim was to assess whether risk of stroke in mid life is associated with cognitive decline over 10 years of follow-up. METHODS: We studied 4153 men and 1657 women (mean age, 55.6 years at baseline) from the Whitehall II study, a longitudinal British cohort study. We used the Framingham Stroke Risk Profile (FSRP), which incorporates age, sex, systolic blood pressure, diabetes mellitus, smoking, prior cardiovascular disease, atrial fibrillation, left ventricular hypertrophy, and use of antihypertensive medication. Cognitive tests included reasoning, memory, verbal fluency, and vocabulary assessed three times over 10 years. Longitudinal associations between FSRP and its components were tested using mixed-effects models, and rates of cognitive change over 10 years were estimated. RESULTS: Higher stroke risk was associated with faster decline in verbal fluency, vocabulary, and global cognition. For example, for global cognition there was a greater decline in the highest FSRP quartile (-0.25 of a standard deviation; 95% confidence interval: -0.28 to -0.21) compared with the lowest risk quartile (P = .03). No association was observed for memory and reasoning. Of the individual components of FSRP, only diabetes mellitus was associated independently with faster cognitive decline (ß = -0.06; 95% confidence interval, -0.01 to 0.003; P = .03). CONCLUSION: Elevated stroke risk at midlife is associated with accelerated cognitive decline over 10 years. Aggregation of risk factors may be especially important in this association.

Bidirectional association between physical activity and symptoms of anxiety and depression: the Whitehall II study.

Although it has been hypothesized that the association of physical activity with depressive and anxiety symptoms is bidirectional, few studies have examined this issue in a prospective setting. We studied this bidirectional association using data on physical activity and symptoms of anxiety and depression at three points in time over 8 years. A total of 9,309 participants of the British Whitehall II prospective cohort study provided data on physical activity, anxiety and depression symptoms and 10 covariates at baseline in 1985. We analysed the associations of physical activity with anxiety and/or depression symptoms using multinomial logistic regression (with anxiety and depression symptoms as dependent variables) and binary logistic regression (with physical activity as the dependent variable). There was a cross-sectional inverse association between physical activity and anxiety and/or depressive symptoms at baseline (ORs between 0.63 and 0.72). In cumulative analyses, regular physical activity across all three data waves, but not irregular physical activity, was associated with reduced likelihood of depressive symptoms at follow-up (OR = 0.71, 95 % CI 0.54, 0.99). In a converse analysis, participants with anxiety and depression symptoms at baseline had higher odds of not meeting the recommended levels of physical activity at follow-up (OR = 1.79, 95 % CI 1.17, 2.74). This was also the case in individuals with anxiety and/or depression symptoms at both baseline and follow-up (OR = 1.70, 95 % CI 1.10, 2.63). The association between physical activity and symptoms of anxiety and/or depression appears to be bidirectional.

Predictive utility of the Framingham general cardiovascular disease risk profile for cognitive function: evidence from the Whitehall II study.

Aims Vascular risk factors are associated with cognitive impairment and dementia, although most of the research in this domain focuses on cerebrovascular factors. We examined the relationship between the recently developed Framingham general cardiovascular risk profile and cognitive function and 10-year decline in late midlife. Methods and results Study sample comprised of 3486 men and 1341 women, mean age 55 years [standard deviation (SD)=6], from the Whitehall II study, a longitudinal British cohort study. The Framingham General Cardiovascular Risk profile, assessed between 1997 and 1999, included age, sex, HDL cholesterol, total cholesterol, systolic blood pressure, smoking status, and diabetes status. Measures of cognitive function consisted of tests of reasoning (Alice Heim 4-I), memory, phonemic and semantic fluency, and vocabulary (Mill-Hill), assessed three times (1997-1999, 2002-2004, 2007-2009) over 10 years. In cross-sectional age-adjusted models, 10% point increments in cardiovascular risk were associated with poor performance in all cognitive domains in both men and women (all P-values <0.001). In models adjusted for age, ethnicity, marital status, and education, 10% higher cardiovascular risk was associated with greater overall 10-year cognitive decline in men, reasoning in particular (-0.47; 95% CI: -0.81, -0.11). Conclusion In middle-aged individuals free of cardiovascular disease, an adverse cardiovascular risk profile is associated with poor cognitive function, and decline in at least one cognitive domain in men.

The burden of osteoporotic fractures beyond acute care: the Canadian Multicentre Osteoporosis Study (CaMos).

BACKGROUND: the burden associated with osteoporotic fractures has commonly been reported in terms of utilisation of acute care. However, individuals with fractures suffer lasting deficits in quality of life and the burden of care extends well beyond the initial acute care period. The burden of fractures related to post-acute heath care utilisation, and informal care giving, has not been sufficiently addressed. We examine the use of formal and informal post-acute care in men and women 50 years and older who sustained fractures. METHODS: the study sample consisted of 1,116 men and women from the Canadian Multicentre Osteoporosis Study (CaMos) who sustained a fracture. We assessed utilisation of post-acute care including rehabilitative and home care services, as well as informal care in persons with a hip, vertebral, or non-hip-non-vertebral fractures. RESULTS: use of rehabilitative and home care services was reported by 37.1% and 18.2% of men and women, respectively. Persons with hip fracture were more likely to report use of these services compared with persons with non-hip-non-vertebral fractures; those with vertebral fracture were less likely to report using these services. Use of informal care was reported by 47.2% of participants. Individuals with multiple fractures made more extensive use of post-acute resources compared with those with single fractures. CONCLUSIONS: use of post-acute care in individuals with fracture is extensive and the contribution of use of these resources to the overall burden of fractures cannot be ignored. Our findings have implications for future economic analyses and policy-making related to care of osteoporotic fractures.

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Association of plasma ß-amyloid with MRI markers of structural brain aging the 3-City Dijon study.

Cerebral ß-amyloid (Aß) deposition and atrophy are central features of Alzheimer disease. Studies of Alzheimer disease biomarkers have largely focused on Aß in cerebrospinal fluid (CSF), and there is uncertainty as to what plasma Aß may be a marker. We examined the association of Aß levels in the plasma with magnetic resonance imaging (MRI)-markers of brain aging, including longitudinal changes in global and regional brain volumes, in dementia-free persons. We studied 1530 participants of the Three-City-Dijon cohort, aged 65-80 years. Plasma Aß measurement and magnetic resonance imaging were performed at baseline and after a 4-year follow up. Total brain, gray matter, and hippocampal volume were estimated using voxel-based morphometry, and annualized change in brain volumes was calculated. Increased plasma Aß1-40 was associated with lower baseline hippocampal volume. Although baseline plasma Aß levels were not associated with longitudinal change in brain volumes, consistently high plasma Aß1-40 levels were associated with faster total brain atrophy and consistently low plasma Aß1-42/Aß1-40 ratio, with increased total brain atrophy and gray matter atrophy. In dementia-free older adults, high plasma Aß1-40 and low plasma Aß1-42/Aß1-40 ratio were associated with smaller hippocampal volume and accelerated global and regional brain atrophy respectively.

Plasma ß-amyloid and MRI markers of cerebral small vessel disease: Three-City Dijon study.

OBJECTIVE: We investigated the relation of circulating plasma ß-amyloid (Aß) with MRI markers of small vessel disease (SVD) in dementia-free community persons. METHODS: Participants were 1,690 individuals aged 65 to 80 years from the Three-City Dijon Study. Plasma Aß measurement and MRI examination were performed at baseline and after a 4-year follow-up. MRI markers of SVD included white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces. We examined the relation of plasma Aß levels with MRI markers of SVD at baseline and with progression of WMH over follow-up (n = 1,057). We also assessed whether these relations were modified by vascular risk factors, notably blood pressure. RESULTS: Low plasma Aß1-40 levels were associated with increased progression of WMH, and low Aß1-42 with higher odds of extensive WMH progression over the follow-up (odds ratio = 1.66, 95% confidence interval = 1.16-2.38). Consistently low Aß1-40 and Aß1-42 levels on both measurements were associated with accelerated progression of WMH. These associations were modified by blood pressure levels but not the APOE ε4 genotype. CONCLUSIONS: Progression of WMH volume in dementia-free older persons is associated with levels of circulating plasma Aß. These results reinforce the notion of an interrelation of vascular and neurodegenerative mechanisms in cerebral aging.

Predicting cognitive decline: a dementia risk score vs. the Framingham vascular risk scores.

OBJECTIVE: Our aim was to compare 2 Framingham vascular risk scores with a dementia risk score in relation to 10-year cognitive decline in late middle age. METHODS: Participants were men and women with mean age of 55.6 years at baseline, from the Whitehall II study, a longitudinal British cohort study. We compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the cardiovascular risk factors, aging and dementia (CAIDE) risk score that uses risk factors in midlife to estimate risk of late-life dementia. Cognitive tests included reasoning, memory, verbal fluency, vocabulary, and global cognition, assessed 3 times over 10 years. RESULTS: Higher cardiovascular disease risk and higher stroke risk were associated with greater cognitive decline in all tests except memory; higher dementia risk was associated with greater decline in reasoning, vocabulary, and global cognitive scores. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline; these differences were statistically significant for semantic fluency and global cognitive scores. For example, cardiovascular disease risk was associated with -0.06 SD (95% confidence interval [CI] = -0.08, -0.05) decline in the global cognitive scores over 10 years whereas dementia risk was associated with -0.03 SD (95% CI = -0.04, -0.01) decline (difference in ß coefficients = 0.03; 95% CI = 0.01, 0.05). CONCLUSIONS: The CAIDE dementia and Framingham risk scores predict cognitive decline in late middle age but the Framingham risk scores may have an advantage over the dementia risk score for use in primary prevention for assessing risk of cognitive decline and targeting of modifiable risk factors.

Obesity phenotypes in midlife and cognition in early old age: the Whitehall II cohort study.

OBJECTIVE: To examine the association of body mass index (BMI) and metabolic status with cognitive function and decline. METHODS: A total of 6,401 adults (71.2% men), aged 39-63 years in 1991-1993, provided data on BMI (normal weight 18.5-24.9 kg/m(2), overweight 25-29.9 kg/m(2); and obese ≥30 kg/m(2)) and metabolic status (abnormality defined as 2 or more of 1) triglycerides ≥1.69 mmol/L or lipid-lowering drugs, 2) systolic blood pressure ≥130 mm Hg, diastolic blood pressure ≥85 mm Hg, or antihypertensive drugs, 3) glucose ≥5.6 mmol/L or medications for diabetes, and 4) high-density lipoprotein cholesterol <1.04 mmol/L for men and <1.29 mmol/L for women). Four cognitive tests (memory, reasoning, semantic, and phonemic fluency) were administered in 1997-1999, 2002-2004, and 2007-2009, standardized to z scores, and averaged to yield a global score. RESULTS: Of the participants, 31.0% had metabolic abnormalities, 52.7% were normal weight, 38.2% were overweight, and 9.1% were obese. Among the obese, the global cognitive score at baseline (p = 0.82) and decline (p = 0.19) over 10 years was similar in the metabolically normal and abnormal groups. In the metabolically normal group, the 10-year decline in the global cognitive score was similar (p for trend = 0.36) in the normal weight (-0.40; 95% confidence interval [CI] -0.42 to -0.38), overweight (-0.42; 95% CI -0.45 to -0.39), and obese (-0.42; 95% CI -0.50 to -0.34) groups. However, in the metabolically abnormal group, the decline on the global score was faster among obese (-0.49; 95% CI -0.55 to -0.42) than among normal weight individuals (-0.42; 95% CI -0.50 to -0.34), (p = 0.03). CONCLUSIONS: In these analyses the fastest cognitive decline was observed in those with both obesity and metabolic abnormality.