Cholesterol metabolism is believed to play a role in the development of Alzheimer’s disease (AD). Oxysterol metabolites of cholesterol, 24S-hydroxycholesterol (24-OHC, a brain-derived oxysterol) and 27-hydroxycholesterol (27-OHC, a peripherally derived oxysterol) cross the blood brain barrier and have been associated with Alzheimer’s disease (AD). We investigated whether oxysterols were associated with markers of cerebrovascular disease prior to the onset of cognitive impairment.

Oxysterols were quantified in 105 participants (average age was 80±4 years) from the Pittsburgh Cardiovascular Health Study Cognition Study (CHS-CS) who remained cognitively normal at blood draw in 2002, had MRI in 1992 and 1998 and annual cognitive assessment for incident AD and mild cognitive impairment (MCI) made by consensus conference between 1998 and 2010.

Higher plasma levels of 24-OHC were associated with age, gender, the presence of high grade white matter hyperintensities (WMH) and brain infarcts on prior MRI. Participants with higher plasma 24-OHC and a greater ratio of 24-OHC/27-OHC were also more likely to develop incident cognitive impairment over 8 years of follow-up.

Higher levels of 24-OHC suggest increased cholesterol metabolism occurring in the brains of participants with cerebrovascular disease prior to the onset of cognitive impairment.

Measurement of oxysterols may provide information about cholesterol metabolism and brain disease over the cognitive impairment process.

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.

Background

Chronic arterial stiffness contributes to the negative health effects of obesity and insulin resistance, which include hypertension, stroke, and increased cardiovascular and all-cause mortality. Weight loss and improved insulin sensitivity are individually associated with improved central arterial stiffness; however, their combined effects on arterial stiffness are poorly understood. The purpose of this study was to determine how insulin levels modify the improvements in arterial stiffness seen with weight loss in overweight and obese young adults.

Methods

To assess the effects of weight loss and decreased fasting insulin on vascular stiffness, we studied 339 participants in the Slow the Adverse Effects of Vascular Aging (SAVE) trial. At study entry, the participants were aged 20–45, normotensive, non-diabetic, and had a body-mass index of 25–39.9 kg/m2. Measures of pulse wave velocity (PWV) in the central (carotid-femoral (cfPWV)), peripheral (femoral-ankle (faPWV)), and mixed (brachial-ankle (baPWV)) vascular beds were collected at baseline and 6 months. The effects of 6-month change in weight and insulin on measures of PWV were estimated using multivariate regression.

Results

After adjustment for baseline risk factors and change in systolic blood pressure, 6-month weight loss and 6-month change in fasting insulin independently predicted improvement in baPWV but not faPWV or cfPWV. There was a significant interaction between 6-month weight change and change in fasting insulin when predicting changes in baPWV (p < 0.001). Individuals experiencing both weight loss and insulin reductions showed the greatest improvement in baPWV.

Conclusions

Young adults with excess weight who both lower their insulin levels and lose weight see the greatest improvement in vascular stiffness. This improvement in vascular stiffness with weight loss and insulin declines may occur throughout the vasculature and may not be limited to individual vascular beds.

Trial registration

NCT00366990