Search tips
Search criteria

Results 1-10 (10)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Ankle-brachial index and inter-artery blood pressure differences as predictors of cognitive function in overweight and obese older adults with diabetes: Results from the Action for Health in Diabetes Movement and Memory Study 
Ankle-brachial index (ABI) and inter-artery systolic blood pressure differences, as markers of vascular disease, are plausible risk factors for deficits in cognitive function among overweight and obese adults with type 2 diabetes.
ABI and maximum inter-artery differences (MIAD) in systolic blood pressures were assessed annually for five years among 479 participants assigned to the control condition in a randomized clinical trial of a behavioral weight loss intervention. A battery of standardized cognitive function tests was administered four to five years later. Analyses of covariance were used to assess relationships that ABI, MIAD, and progression of ABI and MIAD had with cognitive function.
There was a curvilinear relationship between ABI and a composite index of cognitive function (p=0.03), with lower ABI being associated with poorer function. In graded fashions, both greater MIAD and increases in MIAD over time also had modest relationships with poorer verbal memory (both p≤0.05), processing speed (both p≤0.05), and composite cognitive function (both p≤0.04). These relationships were independent of each other and remained evident after extensive covariate adjustment.
In overweight and obese adults with type 2 diabetes, lower ABI and larger inter-artery systolic blood pressure differences have modest, independent, graded relationships with poorer cognitive function 4–5 year later.
PMCID: PMC4964588  PMID: 25546032
Cognitive function; Arterial disease; Diabetes; Obesity
2.  Markers of Cholesterol Transport are Associated with Amyloid Deposition in the Brain 
Neurobiology of aging  2013;35(4):802-807.
Cholesterol is implicated in the development of late onset Alzheimer’s disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using the Pittsburgh Compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, HDLc, LDLc, triglycerides, ApoE, clusterin, oxysterol metabolites of cholesterol and previously reported genes associated with late-onset AD) in 175 non-demented elderly subjects. High Aβ deposition was significantly associated with having a lower mini-mental state exams score (<27, p=0.04), high systolic blood pressure (p=0.04), APOE*4 (p<0.01), lower plasma ApoE levels (p=0.02) and variation in the ABCA7 gene (p=0.02) and EPHA1 genes (p=0.02). Cholesterol measures were not related to Aβ deposition in this cohort of non-demented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. The better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.
PMCID: PMC3896052  PMID: 24199960
3.  Brain Cholesterol Metabolism, Oxysterols, and Dementia 
Cholesterol metabolism is implicated in the etiology of Alzheimer’s disease (AD) and amyloid production in the brain. While brain cholesterol cannot be measured directly in vivo, the oxysterol, 24S-hydroxycholesterol (24-OHC), is the predominant metabolite of brain cholesterol and can be measured in the blood. The aim of this review is to evaluate plasma 24-OHC as a potential biomarker of AD risk and discuss factors related to its levels in the brain and blood. This systematic review examines studies published between 1950 and June 2012 that examined the relationship between plasma 24-OHC, cognition, brain structure, and dementia using the following key words (“24S-hydroxycholesterol” or “24-hydroxycholesterol”) and (“Brain” or “Cognitive”). We found a total of 28 studies of plasma 24-OHC and neurodegenerative disease, including a subset of 12 that used dementia as a clinical endpoint. These studies vary in the direction of the observed associations. Results suggest plasma 24-OHC may be higher in the early stages of cognitive impairment and lower in more advanced stages of AD when compared to cognitively normal controls. Measures of 24-OHC in the blood may be an important potential marker for cholesterol metabolism in the brain and risk of AD. Further studies of plasma 24-OHC and dementia must account for the stage of disease, establish the temporal trends in oxysterol concentrations, and employ neuroimaging modalities to assess the structural and metabolic changes occurring in the brain prior to the onset of cognitive impairment.
PMCID: PMC4354887  PMID: 23076077
Alzheimer’s disease; brain; dementia; 24-hydroxycholesterol; 24S-hydroxycholesterol; oxysterols
4.  Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults 
JAMA neurology  2014;71(5):562-568.
Recent studies show that cerebral β-amyloid (Aβ) deposition is associated with blood pressure and measures of arterial stiffness in nondemented individuals.
To examine the association between measures of arterial stiffness and change in Aβ deposition over time.
Deposition of Aβ was determined in a longitudinal observational study of aging by positron emission tomography using the Pittsburgh compound B twice 2 years apart in 81 nondemented individuals 83 years and older. Arterial stiffness was measured with a noninvasive and automated waveform analyzer at the time closest to the second positron emission tomography scan. All measures were performed under standardized conditions. Pulse wave velocity (PWV) was measured in the central (carotid-femoral and heart-femoral PWV), peripheral (femoral-ankle PWV), and mixed (brachial-ankle PWV) vascular beds.
The change in Aβ deposition over 2 years was calculated from the 81 individuals with repeat Aβ-positron emission tomography.
The proportion of Aβ-positive individuals increased from 48% at baseline to 75% at follow-up. Brachial-ankle PWV was significantly higher among Aβ-positive participants at baseline and follow-up. Femoral-ankle PWV was only higher among Aβ-positive participants at follow-up. Measures of central stiffness and blood pressure were not associated with Aβ status at baseline or follow-up, but central stiffness was associated with a change in Aβ deposition over time. Each standard deviation increase in central stiffness (carotid-femoral PWV, P = .001; heart-femoral PWV, P = .004) was linked with increases in Aβ deposition over 2 years.
This study showed that Aβ deposition increases with age in nondemented individuals and that arterial stiffness is strongly associated with the progressive deposition of Aβ in the brain, especially in this age group. The association between Aβ deposition changes over time and generalized arterial stiffness indicated a relationship between the severity of subclinical vascular disease and progressive cerebral Aβ deposition.
PMCID: PMC4267249  PMID: 24687165
5.  Markers of Cholesterol Metabolism in the Brain Show Stronger Associations with Cerebrovascular Disease than Alzheimer’s Disease 
Journal of Alzheimer's Disease  2012;30(1):53-61.
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.
PMCID: PMC3348402  PMID: 22377780
oxysterols; 24S-hydroxycholesterol; cerebrovascular disease; dementia and Alzheimer’s disease
6.  Review of ‘the potential role of arterial stiffness in the pathogenesis of Alzheimer’s disease’ 
Arterial stiffness is emerging as an important risk marker for poor brain aging and dementia through its associations with cerebral small vessel disease, stroke, β-amyloid deposition, brain atrophy and cognitive impairment. Arterial stiffness directly relates the detrimental effects of hypertension on peripheral organs with dire consequences for the extensive microvasculature structure of the kidneys and brain. In this review, we discuss the evidence linking arterial stiffness, hypertension and brain structural abnormalities in older adults. In particular, we discuss the potential mechanisms linking arterial stiffness to brain β-amyloid deposition and dementia and potential therapeutic strategies to prevent hypertension’s adverse effects on the brain.
PMCID: PMC4423756  PMID: 25894876
Alzheimer’s disease; arterial stiffness; β-amyloid deposition; brain aging; dementia; hypertension
7.  Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults 
Neurology  2013;81(19):1711-1718.
To determine arterial stiffness and β-amyloid (Aβ) deposition in the brain of dementia-free older adults.
We studied a cohort of 91 dementia-free participants aged 83–96 years. In 2009, participants completed brain MRI and PET imaging using Pittsburgh compound B (PiB; a marker of amyloid plaques in human brain). In 2011, we measured resting blood pressure (BP), mean arterial pressure (MAP), and arterial stiffness by pulse wave velocity (PWV) in the central, peripheral, and mixed (e.g., brachial ankle PWV [baPWV]) vascular beds, using a noninvasive and automated waveform analyzer.
A total of 44/91 subjects were Aβ-positive on PET scan. Aβ deposition was associated with mixed PWV, systolic BP, and MAP. One SD increase in baPWV resulted in a 2-fold increase in the odds of being Aβ-positive (p = 0.007). High white matter hyperintensity (WMH) burden was associated with increased central PWV, systolic BP, and MAP. Compared to Aβ-negative individuals with low WMH burden, each SD increase in PWV was associated with a 2-fold to 4-fold increase in the odds of being Aβ-positive and having high WMH.
Arterial stiffness was associated with Aβ plaque deposition in the brain, independent of BP and APOE ε4 allele. The associations differed by type of brain abnormality and vascular bed measured (e.g., WMH with central stiffness and Aβ deposition and mixed stiffness). Arterial stiffness was highest in individuals with both high Aβ deposition and WMH, which has been suggested to be a “double hit” contributing to the development of symptomatic dementia.
PMCID: PMC3812104  PMID: 24132374
8.  Frontal Gray Matter Atrophy in Middle Aged Adults with Type 1 Diabetes is Independent of Cardiovascular Risk Factors and Diabetes Complications 
Journal of diabetes and its complications  2013;27(6):10.1016/j.jdiacomp.2013.07.001.
To determine if regional gray matter volume (GMV) differences in middle-aged adults with and without type-1 diabetes (T1D) are localized in areas most vulnerable to aging, e.g. fronto-subcortical networks; and if these differences are explained by cardiovascular risk factors and diabetes complications.
Regional GMV was computed using 3 Tesla MRI of 104 adults with a childhood onset of T1D (mean age: 49+7 and duration: 41±6 years) and 151 adults without diabetes (mean age: 40+6). A Bonferroni threshold (n=45, p≤0.001) was applied to account for multiple between-group comparisons and analyses were repeated in an age- and gender-matched subset of participants with T1D and controls (n=44 in each group, mean age [SD] and range: 44.0, [4.3], 17.4 and 44.6 [4.3], 17.0, respectively).
Compared to controls, T1D patients had smaller GMV in the frontal lobe (6 to 19% smaller) and adjacent supramarginal and postcentral gyri (8 to 13% smaller). Between-group differences were independent of age, waist circumference, systolic blood pressure, fasting total cholesterol and smoking status and were similar in sensitivity analyses restricted to age- and gender-matched participants. Associations between GMV and diabetes complications were not significant.
These findings extend the notion of accelerated brain aging in T1D to middle-aged adults. The pathophysiology of frontal gray matter atrophy and its impact on future development of disability and dementia need further study, especially as middle-aged T1D patients progress to older age.
PMCID: PMC3818288  PMID: 23994432
Brain; Imaging (MRI); Complications; Retinopathy; Nephropathy; Hypertension
9.  Microinfarcts, brain atrophy, and cognitive function: the HAAS autopsy study 
Annals of neurology  2011;70(5):774-780.
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.
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.
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.
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.
PMCID: PMC3241005  PMID: 22162060
10.  Effects of weight loss and insulin reduction on arterial stiffness in the SAVE trial 
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.
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.
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.
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
PMCID: PMC3468408  PMID: 22998737
Pulse wave velocity; Insulin; Weight loss and arterial stiffness

Results 1-10 (10)