Search

Background: the risk apolipoprotein E-4 (APOE4) poses for mild cognitive impairment (MCI) may vary based on the neuropsychological definition of MCI. Setting: a community-based cohort study. Methods: using two psychometric neuropsychological impairment definitions, we examined APOE4 and prevalent MCI among older adults or pre-MCI among middle-aged adults. Neuropsychological, clinical and genetic data were collected on 2,239 Framingham Offspring Cohort participants free from clinical stroke or dementia (62 ± 9 years; 54% women). Prevalent amnestic MCI was defined from neuropsychological performances ≥1.5 SD below the mean based on (i) age and education or (ii) age and Wide Range Achievement Test-3 Reading (WRAT-3 Reading) performance adjustment. Results: in the entire sample, multivariable-adjusted logistic regressions found that APOE4 was associated with amnestic MCI when using the age and WRAT Reading definition (odds ratio [OR] = 1.7, P = 0.002) but not the age and education definition (OR = 1.0, P = 0.90). Results were modified by age, such that APOE4 was associated with amnestic MCI in participants ≥65 years using both the age and WRAT Reading definition (OR = 2.4, P < 0.001) and the age and education definition (OR = 1.7, P = 0.04). Conclusion: APOE4 risk for prevalent amnestic MCI varies depending on the definition of objective neuropsychological impairment for MCI. Our findings support existing literature emphasising the need to refine MCI neuropsychological profiling methods.

Background: offspring of long-lived individuals have lower risk for dementia. We examined the relation between parental longevity and cognition and subclinical markers of brain ageing in community-dwelling adult offspring. Methods: offspring participants with both parents in the Framingham Heart Study, aged ≥55 years and dementia-free underwent baseline and repeat neuropsychological (NP) testing and brain magnetic resonance imaging (MRI). Parental longevity was defined as having at least one parent survive to age ≥85 years. To test the association between parental longevity and measures of cognition and brain volumes, we used multivariable linear and logistic regression adjusting for age, sex, education and time to NP testing or brain MRI. Results: of 728 offspring (mean age 66 years, 54% women), 407 (56%) had ≥1 parent achieve longevity. In cross-sectional analysis, parental longevity was associated with better scores on attention (beta 0.21 ± 0.08, P = 0.006) and a lower odds of extensive white matter hyperintensity on brain MRI (odds ratio 0.59, 95% CI: 0.38, 0.92, P = 0.019). The association with white matter hyperintensity was no longer significant in models adjusted for cardiovascular risk factors and disease. In longitudinal analysis (6.7 ± 1.7 years later), offspring with parental longevity had slower decline in attention (0.18 ± 0.08, P = 0.038), executive function (beta 0.19 ± 0.09, P = 0.031) and visual memory (beta −0.18 ± 0.08, P = 0.023), and less increase in temporal horn volume (beta −0.25 ± 0.09, P = 0.005). The associations persisted in fully adjusted models. Conclusion: parental longevity is associated with better brain ageing in middle-aged offspring.

The transition from normal aging to mild cognitive impairment to Alzheimer disease (AD) is often indistinct. Imaging studies suggest early changes in posterior brain regions, including posterior temporoparietal and occipital cortex, but pathologic studies show initial changes in the medial temporal lobe with progressive neocortical involvement as cognition deteriorates. We evaluated the regional distribution of AD pathology in 41 elderly brain donors from the Framingham Heart Study who were cognitively intact, mildly impaired, or demented on the basis of probable AD. We found that 52% of the cognitively intact subjects, and all subjects with mild cognitive impairment or dementia, had dense neurofibrillary tangles (NFTs), neuropil threads, and tau-immunoreactive neurites surrounding neuritic plaques (NPs) in visual association cortex Brodmann area 19. All cognitively intact subjects with area 19 NFTs also had dense core NP and beta amyloid (Abeta) angiopathy in area 19. Area 19 pathology was occasionally present in the absence of substantial pathology in the hippocampus or entorhinal cortex and was not correlated with medial temporal lobe pathology. Dense AD pathology in area 19 is present in some cognitively intact subjects with preclinical AD. The unique metabolic, connectional, and vascular features of this region may confer enhanced vulnerability to neurodegeneration.

Plasma total homocysteine (tHcy) concentrations are associated with deficits in cognitive performance in persons free from dementia. The extent to which age modifies these associations is in need of further investigation in large, community-based, prospective studies combining the following elements: 1) multiple cognitive tests; 2) statistical adjustment for the role of the vitamin cofactors folate, vitamin B6, and vitamin B12; and 3) adjustment for the presence of risk factors for cardiovascular disease and stroke. Using data collected between 1991 and 2002, the authors investigated the associations between tHcy and multiple measures of cognitive performance in 2,096 dementia- and stroke-free participants of the Framingham Offspring Study, who were stratified into three age groups (40-49 years, 50-59 years, 60-82 years), after findings of statistically significant tHcy-by-age interactions for multiple cognitive measures. Regardless of statistical adjustment for age, sex, gender, the vitamin cofactors, and cardiovascular risk factors, statistically significant inverse associations between tHcy and multiple cognitive domains were observed for individuals aged 60 or more years; no such associations were observed for participants aged less than 60 years. Early preventive interventions may be important, because the inverse association between tHcy and cognitive performance is observed beyond middle age.

The ankle-brachial index (ABI) is widely used in the clinical diagnosis of peripheral arterial disease. The contributions of genetic and environmental influences to normal and abnormal ABI values are unknown. In this study, the authors used available data on 94 monozygotic pairs and 90 dizygotic pairs of elderly, White, male twins examined in 1995-1997 to investigate the contributions of genetic and environmental influences to normative ABI values. Within-twin-pair correlations for normative ABI values were statistically significant, and the correlation in monozygotic twin pairs was significantly greater than that in dizygotic pairs. Structural equation modeling of the variance-covariance matrices of monozygotic and dizygotic twins indicated that 48% of the observed variability in ABI values could be attributed to additive genetic effects. In contrast, concordance rates for low ABI values (ABI< or =0.9) for both monozygotic and dizygotic twins were significantly greater than would be expected by chance alone, but within-pair monozygotic similarity was not significantly greater than dizygotic similarity. A matched-cotwin analysis in 21 pairs that were discordant for low ABI values found that twins with low ABI values were physically less active and more likely to be persistent smokers than their normal-control brothers. These findings reinforce the role of individual health practices (e.g., physical activity, smoking) in the manifestation of peripheral arterial disease among subjects matched for age, genetics, and early shared environment.

Cognitive decline and poor physical function are risk factors for disability in old age and may occur more often in subjects with the apolipoprotein E epsilon4 (ApoE-epsilon4) allele. The objective of this study was to investigate the joint effect of ApoE-epsilon4 and structural changes detected on MRI brain scans on cognitive decline and lower-extremity function.Brain MRI (1.5 T), neuropsychological tests, and lower-extremity physical function tests were administered to World War II male veteran twins ages 69 to 80. Quantification of MRI scans used a previously published algorithm to segment brain images into total cerebral brain (TCB), cerebrospinal fluid (CSF), and white-matter hyperintensity (WMH) volumes. A short battery of physical performance tests was used to assess lower-extremity function. Ten-year changes in performance on the Mini-Mental State Exam (MMSE), the Benton Visual Retention Test (BVRT), and the Digit Symbol Substitution (DSS) test were used to assess cognitive decline.For the sample as a whole, the comparison of subjects by median split of total cerebral brain volume found that those with brain volumes below the median performed worse on tests of gait and balance (p.01) and experienced greater cognitive decline on the MMSE and BVRT cognitive test batteries (both p.01). In addition, subjects with WMH volumes above the median had poor performance on the standing balance tasks and experienced greater decline on the DSS test (p.01). Stratified analyses revealed that the joint effect of radiological findings and the ApoE-epsilon4 allele on cognitive decline and lower-extremity function was often greater than that expected from the separate effects combined.We conclude that radiological findings in conjunction with ApoE-epsilon4 may single out a group at higher risk for dementia. We speculate that the observed interaction effect may be due to increased susceptibility to brain injury or impaired repair mechanisms in subjects with ApoE-epsilon4.

Tests of balance, gait, and endurance were administered to 95 monozygotic (MZ) and 92 dizygotic (DZ), white male twins aged 68 to 79 years who had been born in the United States. Within-twin-pair correlations were calculated for each individual task and for an overall summary performance score. These were subjected to structural equation modeling to determine the contributions of genetic and environmental influences to individual differences in performance scores. MZ intraclass correlations were significant and greater than DZ correlations for the 8-foot walk and the repeated chair stands task, but not for the standing balance task. The heritability of the lower-extremity summary score was 57%, of which 39% was due to additive genetic effects and 18% due to nonadditive effects. In addition, we found that genetic influences contributed primarily to twin similarity in the poorest quartile of performance, whereas shared environmental influences contributed to twin similarity in the best quartile. Language: en

The authors prospectively examined the influence of increased levels of physical activity on risk of stroke in members of the Framingham Study cohort. Two separate analyses were performed, one during midlife in 1,897 men (mean age = 49.7 years) and 2,299 women (mean age = 49.9 years) and another when the cohort was older (1,361 men (mean age = 63.0) and 1,862 women (mean age = 63.7)). A structured questionnaire administered at two separate examinations was used to estimate the amount of metabolic work done during a typical 24-hour period. Physical activity was categorized into tertiles, and medium and high levels of physical activity were compared with a low level of physical activity, which was used as the referent group. Cox proportional hazards, life table, and time-dependent covariate analyses were used to examine the relation between level of physical activity and stroke risk over a follow-up period of up to 32 years. In men, adjusted analyses revealed that increased levels of physical activity were protective. The strongest effect was obtained from an analysis involving older cohort members in the medium tertile (risk ratio = 0.41, 95% confidence interval 0.24-0.69). High levels of physical activity did not confer an additional benefit over medium levels. Adjusted analyses showed no significant protective effect in women. These results indicate that medium and high levels of physical activity among men are protective against stroke relative to low levels.

It was hypothesized that blood pressure would be inversely related to cognitive functioning, if unconfounded with antihypertensive medication and measured over many occasions prior to neuropsychological testing. For stroke-free Framingham Study participants aged 55-88 years (n = 1,702), blood pressure levels were averaged over five biennial examinations (1956-1964) when few hypertensives were being treated, and examined in relation to neuropsychological tests administered between 1976 and 1978. With age, education, occupation, cigarette smoking, alcohol consumption, and gender controlled, blood pressure levels and chronicity of hypertension were inversely related to the composite score and measures of attention and memory. This was true for the full sample, for a subsample untreated during blood pressure measurement (n = 1,485), and for a subsample untreated throughout the entire study period (n = 1,038). For example, decline per 10 mmHg increment in blood pressure ranged from -0.04 to -0.07 standard score units (z) for the composite score. A negative finding previously was most likely due to blood pressure measurement concurrently with neuropsychological testing, or too few measurements. Hypertension-associated pathogenic processes may cause mild cognitive impairment, but other mechanisms need to be considered.

In 1976-1978, a battery of eight neuropsychologic tests were administered to 2,123 participants in the Framingham Study who were aged 55-89 years. Performance on each test was examined in relation to concurrently measured systolic and diastolic blood pressure while controlling for age, sex, education, antihypertensive medication, alcohol consumption, and smoking. Those with a diagnosis of stroke were excluded from the analysis. In the remaining sample of 2,032, neither blood pressure nor antihypertensive treatment was significantly associated with cognitive performance. Even after excluding persons on antihypertensive medication, blood pressure was still unrelated to cognitive performance. In contrast to other studies, the authors found no consistent relation between blood pressure and cognitive performance.