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1.  Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults 
JAMA neurology  2014;71(5):562-568.
IMPORTANCE
Recent studies show that cerebral β-amyloid (Aβ) deposition is associated with blood pressure and measures of arterial stiffness in nondemented individuals.
OBJECTIVE
To examine the association between measures of arterial stiffness and change in Aβ deposition over time.
DESIGN, SETTING, AND PARTICIPANTS
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.
MAIN OUTCOMES AND MEASURES
The change in Aβ deposition over 2 years was calculated from the 81 individuals with repeat Aβ-positron emission tomography.
RESULTS
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.
CONCLUSIONS AND RELEVANCE
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.
doi:10.1001/jamaneurol.2014.186
PMCID: PMC4267249  PMID: 24687165
2.  Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults 
Neurology  2013;81(19):1711-1718.
Objective:
To determine arterial stiffness and β-amyloid (Aβ) deposition in the brain of dementia-free older adults.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/01.wnl.0000435301.64776.37
PMCID: PMC3812104  PMID: 24132374
3.  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.
Aims
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1016/j.jdiacomp.2013.07.001
PMCID: PMC3818288  PMID: 23994432
Brain; Imaging (MRI); Complications; Retinopathy; Nephropathy; Hypertension
4.  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.
doi:10.3233/JAD-2012-111460
PMCID: PMC3348402  PMID: 22377780
oxysterols; 24S-hydroxycholesterol; cerebrovascular disease; dementia and Alzheimer’s disease
5.  Microinfarcts, brain atrophy, and cognitive function: the HAAS autopsy study 
Annals of neurology  2011;70(5):774-780.
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.
doi:10.1002/ana.22520
PMCID: PMC3241005  PMID: 22162060
6.  Effects of weight loss and insulin reduction on arterial stiffness in the SAVE trial 
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
doi:10.1186/1475-2840-11-114
PMCID: PMC3468408  PMID: 22998737
Pulse wave velocity; Insulin; Weight loss and arterial stiffness

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