Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: The ARIC MRI Study
Strokes, vascular risk factors, and apolipoprotein E (APOE) genotype are associated with cognitive decline in the elderly, but definitive evidence that these affect cognition as early as middle age is limited.
We describe the relationships of APOE genotype, stroke, and vascular risk factors with cognitive change over a 14-year follow-up in the Atherosclerosis Risk in Communities (ARIC) Study cohort recruited while in middle age.
Participants included a subset of the ARIC Study who underwent assessments of cognitive function and vascular risk factors. Four cognitive assessments were performed between 1990-1992 and 2004-2006. Cognitive assessments included the Delayed Word Recall (DWR) Test, the Digit Symbol Substitution (DSS) Test, and the Word Fluency (WF) Test. Vascular risk factors were assessed during the baseline visit in 1990-1992. Incident stroke was recorded over the 14 years of follow-up.
There were 1130 participants (mean age, 59 +/- 4.3 [SD] years; 62% women; 52% African-American) with longitudinal data. In multivariate, random-effects linear models adjusted for age, education, gender, and race, the risk factors diabetes and APOE epsilon4 genotype were independently associated with a decline in performance on the DSS test (both P < .005), whereas hypertension and stroke were not. For DWR, stroke and APOE epsilon4 genotype were independent predictors of decline (both P < .001). For the WF test, metabolic syndrome, hypertension, and stroke were independently associated with decline (all P < .005). No evidence of differential effects of risk factors on cognitive decline by race, gender, or interactions between risk factors was found.
The vascular risk factors diabetes and hypertension, a history of stroke itself, and APOE epsilon4 genotype independently contribute to cognitive decline in late middle age and early elderly years.
Available from: Louise Robinson
- "Almost all studies used different tests to assess memory and executive performance whereas more than 80% of the studies used the MMSE for the assessment of global cognitive function. Four studies utilized BMI rather than waist circumference as a measure of obesity in the MetS diagnosis    . The exclusion of these four studies had no effect on the pooled cognitive estimates. "
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ABSTRACT: Background: Metabolic syndrome (MetS) is associated with an increased risk of coronary heart diseases and stroke. Results on the association of MetS with dementia and cognitive decline have been inconsistent. Objective: The aim of this study was to examine the association between MetS and longitudinal changes in cognitive function. Methods: Medline, EMBASE, and Scopus databases were searched from inception to June 2013. Longitudinal cohort studies that reported on the association between MetS and change in cognitive function (over two or more time points), were included. Results: Random-effects models were used to assess the pooled effect sizes of longitudinal changes in cognitive function associated with MetS. Thirteen studies were included. The total sample size was 19,522 subjects. Follow up duration ranged from 1 to 16 years. In the total sample, a small association of MetS with cognitive decline was observed (SDM 0.06, 95%CI: -0.001, 0.12; p = 0.05). When age-stratified, a marginal significant association between MetS and cognitive decline was observed in the younger old group (≤70 years; SDM = 0.09, 95%CI: -0.003, 0.19; p = 0.05) but not in the older group (>70 years; SDM = 0.03, 95%CI: -0.05, 0.11; p = 0.48). The meta-regression showed that duration of follow up was not associated with changes in cognitive estimates (β = 0.005; p = 0.30). Conclusions: Age appears to modify the association between MetS and cognitive decline. These results emphasize the importance of age-stratified risk prediction models of dementia in subjects with chronic metabolic disorders.
Available from: John Patrick Grady
- "The NMDAS permits quantitative analysis of both general and system-specific disease progression and has already been used in assessment of clinical progression in patients with the m.3243A4G mitochondrial DNA mutation, although this was not a longitudinal study (Whittaker et al., 2009). Linear mixed modelling has been widely used to understand disease progression in other neurodegenerative conditions including dementia (Tornatore and Grant, 2002; Hassing et al., 2004; Galvin Je and et al., 2005; Johnson et al., 2009; Knopman et al., 2009; den Heijer et al., 2010), Parkinson's disease (Nandhagopal et al., 2009; Dobkin et al., 2011; Johnson and Galvin, 2011; Vu et al., 2012) and multiple sclerosis (Meier et al., 2007), and NMDAS facilitates such longitudinal modelling of mitochondrial disease progression. "
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ABSTRACT: Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression.
Available from: Archana Singh-Manoux
- "Among individual risk factors, only diabetes was associated independently with cognitive decline. Although this association has not been found in some studies , the observed relation between diabetes and cognitive decline in our study is supported by a number of studies reporting associations of diabetes with longitudinal changes on magnetic resonance imaging markers of vascular brain injury , incident cognitive impairment and cognitive decline   , and incident dementia . There is compelling evidence for a causal relationship between alterations in glycemic control and subsequent brain ischemic and atrophic changes . "
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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.
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.
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 (β = -0.06; 95% confidence interval, -0.01 to 0.003; P = .03).
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.
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