Timothy M. Hughes

Lowering Midlife Levels of Systolic Blood Pressure as a Public Health Strategy to Reduce Late-Life Dementia: Perspective From the Honolulu Heart Program/Honolulu Asia Aging Study

To estimate the potential benefits of lowering systolic blood pressure (SBP) toward preventing late-life dementia, we estimated the population-attributable risk of elevated SBP for dementia. Analyses are based on the cohort of 8006 Japanese American men (born 1900–1919) followed since 1965 as a part of the Honolulu Heart Program, continued as the Honolulu Asia Aging Study. Midlife cardiovascular risk factors and late-life brain function are well described. We estimated the population-attributable risk of dementia cases attributed to midlife SBP, grouped by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria (<120, 120 to <140, and ≥140 mm Hg), taking into account treatment history, confounding factors, and competitive risk for death. The analysis is based on 7878 subjects, including 491 cases of dementia, with a mean interval of 25 years between measurement of blood pressure and dementia diagnosis. Compared with those with SBP <120 mm Hg, untreated, and <50 years of age at baseline, 17.7% (95% CI: 4.6% to 29.1%) of the cases were attributable to prehypertensive levels (SBP: 120 to <140 mm Hg) of SBP, translating into 11 excess cases per 1000. Among those who did not report taking antihypertensive medication in midlife, 27% (95% CI: 8.9% to 42.1%) of dementia cases can be attributed to systolic BP ≥120 mm Hg, translating into 17 excess cases per 1000. Although population-attributable risk estimates for population subgroups may differ by relative risk for dementia or prevalence of elevated levels of blood pressure, these data suggest that reducing midlife systolic BP is an effective prevention strategy to reduce risk for late-life dementia.

Pulse wave velocity is associated with β-amyloid deposition in the brains of very elderly adults

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.

Arterial Stiffness and β-Amyloid Progression in Nondemented Elderly Adults

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.

Markers of cholesterol transport are associated with amyloid deposition in the brain

Cholesterol is implicated in the development of late-onset Alzheimers disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.

Hypertension and Its Role in Cognitive Function: Current Evidence and Challenges for the Future

This review summarizes evidence from studies of blood pressure and dementia-related biomarkers into our understanding of cognitive health and highlights the challenges facing studies, particularly randomized trials, of hypertension and cognition. Several lines of research suggest that elevated blood pressure, especially at midlife, is associated with cognitive decline and dementia and that treatment of hypertension could prevent these conditions. Further, studies of hypertension and brain structure show that blood pressure is associated with several forms of small vessel disease that can result in vascular dementia or interact with Alzheimers pathology to lower the pathologic threshold at which Alzheimers signs and symptoms manifest. In addition, recent studies of hypertension and Alzheimers biomarkers show that elevated blood pressure and pulse pressure are associated with the extent of brain beta amyloid (Aβ) deposition and altered cerebral spinal fluid profiles of Aβ and tau indicative of Alzheimers pathology. However, in spite of strong evidence of biological mechanisms, results from randomized trials of antihypertensive therapy for the prevention of cardiovascular or cerebrovascular disease that include cognitive endpoints do not strongly support the observational evidence that treatment of hypertension should be better for cognition. We propose that future clinical trials should consider including dementia biomarkers and assess genetic and cardiometabolic risk factors that have been associated with progression of the underlying disease pathology to help bridge these gaps.

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 hypertensions adverse effects on the brain.

Diabetic Microvascular Disease: An Endocrine Society Scientific Statement

Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.

The role of insulin in the vascular contributions to age-related dementia.

In addition to its well-known role in energy metabolism in the body, insulin is a vasoactive hormone that regulates peripheral and cerebral blood flow and neuronal function. Vascular and metabolic dysfunctions are emerging risk factors for Alzheimers disease (AD) and age-related dementias, and recent evidence suggests that the two pathways are constitutive and interrelated. As a result, an emphasis on correcting metabolic disorders is emerging as an important strategy in the treatment and prevention of age-related cognitive impairment and AD. We review the evidence regarding the unique and interactive effects of vascular and metabolic disorders in pathological brain aging, with special consideration of the role of insulin dysregulation in promoting AD pathologic processes and vascular brain injury. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Correlation of Echocardiographic Findings With Cerebral Infarction in Elderly Adults. The AGES-Reykjavik Study

Background and Purpose— Chronic effects of hypertension may be observed in multiple end organs. Previous reports suggest that cardiovascular morphological features can mirror cerebral infarction. In this cross-sectional analysis of elderly subjects, we investigated the relationship of a comprehensive set of echocardiographic measures with cerebral infarction detected by MRI. Methods— We compared echocardiographically determined left ventricular (LV) mass, left atrial volume, aortic root diameter, mitral annular calcification, and measures of diastolic function with cerebral infarction determined by MRI using logistic regression in a random sample drawn from the Age Gene/Environment Susceptibility–Reykjavik Study cohort. The model was first adjusted for age and gender, and then for age, gender, and vascular risk factors. Results— Among 692 subjects aged 75 (standard deviation, 6) years, 28% had at least 1 cerebral infarct. When adjusted for age and gender, the presence of cerebral infarction was modestly related to LV mass (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00–1.02) and left atrial volume (OR, 1.03; 95% CI, 1.01–1.05), as well as the lowest quartile of early-to-late pulsed Doppler velocity ratio (early-to-late pulsed Doppler velocity ratio <0.75; OR, 1.87; 95% CI, 1.22–2.87). The latter relation remained significant after adjustment for vascular risk factors and LV ejection fraction (OR, 1.82; 95% CI, 1.16–2.86). Conclusion— Of all echocardiographic parameters, LV filling abnormality as indicated by low early-to-late pulsed Doppler velocity ratio displayed the strongest association with cerebral infarction and this relationship was independent of vascular risk factors. This simple marker of cerebral infarction may be useful when evaluating older patients.

Arterial stiffness and dementia pathology: Atherosclerosis Risk in Communities (ARIC)-PET Study

Objective Arterial stiffness has been associated with evidence of cerebral small vessel disease (cSVD) and fibrillar β-amyloid (Aβ) deposition in the brain. These complex relationships have not been examined in racially and cognitively diverse cohorts. Methods The Atherosclerosis Risk in Communities (ARIC)–Neurocognitive Study collected detailed cognitive testing for adjudication of dementia and mild cognitive impairment (MCI), brain MRI, and arterial stiffness by pulse wave velocity (PWV, carotid-femoral [cfPWV] and heart-carotid [hcPWV]). The ARIC-PET ancillary study added Aβ imaging using florbetapir ([18F]-AV-45) to obtain standardized uptake volume ratios and defined global Aβ-positivity as standardized uptake volume ratio >1.2. One-SD increase in PWV was related to brain volume, MRI-defined cSVD (e.g., cerebral microbleeds and white matter hyperintensity), and cortical Aβ deposition adjusted for age, body mass index, sex, race, and APOE ε4 status. We examined the cross-sectional relationships including interactions by race, APOE ε4 status, and cognition. Results Among the 320 ARIC-PET participants (76 [5] years, 45% black, 27% MCI), greater central stiffness (hcPWV) was associated with greater Aβ deposition (odds ratio [OR] = 1.31, 95% confidence interval [CI] 1.01–1.71). Greater central stiffness (cfPWV) was significantly associated with having lower brain volumes in Alzheimer disease–susceptible regions (in mm3, β = −1.5 [0.7 SD], p = 0.03) and high white matter hyperintensity burden (OR = 1.6, 95% CI 1.2–2.1). Furthermore, cfPWV was associated with a higher odds of concomitant high white matter hyperintensity and Aβ-positive scans (OR = 1.4, 95% CI 1.1–2.1). These associations were strongest among individuals with MCI and did not differ by race or APOE ε4 status. Conclusions Arterial stiffness, measured by PWV, is an emerging risk factor for dementia through its repeated relationships with cognition, cSVD, and Aβ deposition.