Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood.
To determine if midlife ...vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET).
The Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015.
Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level.
Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable.
Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 50.9% participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio OR, 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% n = 20, 50.4% n = 62, and 61.2% n = 82, respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69).
An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.
ARIC (Atherosclerosis Risk In Communities) initiated community-based surveillance in 1987 for myocardial infarction and coronary heart disease (CHD) incidence and mortality and created a prospective ...cohort of 15,792 Black and White adults ages 45 to 64 years. The primary aims were to improve understanding of the decline in CHD mortality and identify determinants of subclinical atherosclerosis and CHD in Black and White middle-age adults. ARIC has examined areas including health disparities, genomics, heart failure, and prevention, producing more than 2,300 publications. Results have had strong clinical impact and demonstrate the importance of population-based research in the spectrum of biomedical research to improve health.
Recent studies using untargeted metabolomics approaches have suggested that plasma branched-chain amino acids (BCAAs) are associated with incident diabetes. However, little is known about the role of ...plasma BCAAs in metabolic abnormalities underlying diabetes and whether these relationships are consistent across ethnic populations at high risk for diabetes. We investigated the associations of BCAAs with insulin sensitivity (SI), acute insulin response (AIR), and metabolic clearance of insulin (MCRI) in a multiethnic cohort.
In 685 participants without diabetes of the Insulin Resistance Atherosclerosis Study (IRAS) (290 Caucasians, 165 African Americans, and 230 Hispanics), we measured plasma BCAAs (sum of valine, leucine, and isoleucine) by mass spectrometry and SI, AIR, and MCRI by frequently sampled intravenous glucose tolerance tests.
Elevated plasma BCAAs were inversely associated with SI and MCRI and positively associated with fasting insulin in regression models adjusted for potential confounders (β = -0.0012 95% CI -0.0018, -0.00059, P < 0.001 for SI; β = -0.0013 95% CI -0.0018, -0.00082, P < 0.001 for MCRI; and β = 0.0015 95% CI 0.0008, 0.0023, P < 0.001 for fasting insulin). The association of BCAA with SI was significantly modified by ethnicity, with the association only being significant in Caucasians and Hispanics. Elevated plasma BCAAs were associated with incident diabetes in Caucasians and Hispanics (multivariable-adjusted odds ratio per 1-SD increase in plasma BCAAs: 1.67 95% CI 1.21, 2.29, P = 0.002) but not in African Americans. Plasma BCAAs were not associated with SI-adjusted AIR.
Plasma BCAAs are associated with incident diabetes and underlying metabolic abnormalities, although the associations were generally stronger in Caucasians and Hispanics.
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.
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 (
F-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
ε4 status. We examined the cross-sectional relationships including interactions by race,
ε4 status, and cognition.
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 mm
, β = -1.5 0.7 SD,
= 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
ε4 status.
Arterial stiffness, measured by PWV, is an emerging risk factor for dementia through its repeated relationships with cognition, cSVD, and Aβ deposition.
Type 2 diabetes is associated with dementia risk, but evidence is limited for possible associations of diabetes and prediabetes with cognitive decline.
To determine whether diabetes in midlife is ...associated with 20-year cognitive decline and to characterize long-term cognitive decline across clinical categories of hemoglobin A1c (HbA1c) levels.
Prospective cohort study.
The community-based ARIC (Atherosclerosis Risk in Communities) study.
13,351 black and white adults aged 48 to 67 years at baseline (1990 to 1992).
Diabetes was defined by self-reported physician diagnosis or medication use or HbA1c level of 6.5% or greater. Undiagnosed diabetes, prediabetes, and glucose control in persons with diagnosed diabetes were defined by clinical categories of HbA1c level. Delayed word recall, digit symbol substitution, and word fluency tests were used to assess cognitive performance and were summarized with a global Z score.
Diabetes in midlife was associated with a 19% greater cognitive decline over 20 years (adjusted global Z-score difference, -0.15 ;95% CI, -0.22 to -0.08;) compared with no diabetes. Cognitive decline was significantly greater among persons with prediabetes (HbA1c level of 5.7% to 6.4%) than among those with an HbA1c level less than 5.7%. Participants with poorly controlled diabetes (HbA1c level ≥ 7.0%) had greater decline than those whose diabetes was controlled (adjusted global Z-score difference, -0.16; P = 0.071). Longer-duration diabetes was also associated with greater late-life cognitive decline (P for trend < 0.001). Rates of decline did not differ significantly between white and black persons (P for interaction = 0.44).
Single HbA1c measurement at baseline, 1 test per cognitive domain, and potential geographic confounding of race comparisons.
Diabetes prevention and glucose control in midlife may protect against late-life cognitive decline.
National Institutes of Health.
Aims/hypothesis
Metabolomic profiling offers the potential to reveal metabolic pathways relevant to the pathophysiology of diabetes and improve diabetes risk prediction.
Methods
We prospectively ...analysed known metabolites using an untargeted approach in serum specimens from baseline (1987–1989) and incident diabetes through to 31 December 2015 in a subset of 2939 Atherosclerosis Risk in Communities (ARIC) study participants with metabolomics data and without prevalent diabetes.
Results
Among the 245 named compounds identified, seven metabolites were significantly associated with incident diabetes after Bonferroni correction and covariate adjustment; these included a food additive (erythritol) and compounds involved in amino acid metabolism isoleucine, leucine, valine, asparagine, 3-(4-hydoxyphenyl)lactate and glucose metabolism (trehalose). Higher levels of metabolites were associated with increased risk of incident diabetes (HR per 1 SD increase in isoleucine 2.96, 95% CI 2.02, 4.35,
p
= 3.18 × 10
−8
; HR per 1 SD increase in trehalose 1.16, 95% CI 1.09, 1.25,
p
= 1.87 × 10
−5
), with the exception of asparagine, which was associated with a lower risk of diabetes (HR per 1 SD increase in asparagine 0.78, 95% CI 0.71, 0.85,
p
= 4.19 × 10
−8
). The seven metabolites modestly improved prediction of incident diabetes beyond fasting glucose and established risk factors (C statistics 0.744 vs 0.735,
p
= 0.001 for the difference in C statistics).
Conclusions/interpretation
Branched chain amino acids may play a role in diabetes development. Our study is the first to report asparagine as a protective biomarker of diabetes risk. The serum metabolome reflects known and novel metabolic disturbances that improve prediction of diabetes.
The contribution of cardiovascular dysfunction to frailty in older adults is uncertain. This study aimed to define the relationship between frailty and cardiovascular structure and function, and ...determine whether these associations are independent of coexisting abnormalities in other organ systems.
We studied 3,991 older adults (mean age 75.6±5.0 years; 59% female) from the Atherosclerosis Risk in Communities (ARIC) Study in whom the following six organ systems were uniformly assessed: cardiac (by echocardiography), vascular (by ankle-brachial-index and pulse-wave-velocity), pulmonary (by spirometry), renal (by estimated glomerular filtration rate), hematologic (by hemoglobin), and adipose (by body mass index and bioimpedance). Frailty was defined by the presence of ≥3 of the following: low strength, low energy, slowed motor performance, low physical activity, or unintentional weight loss.
Two hundred eleven (5.3%) participants were frail. In multivariable analyses adjusted for demographics, diabetes, hypertension, and measures of other organ system function, frailty was independently and additively associated with left ventricular hypertrophy (odds ratio OR = 1.72; 95% confidence interval CI = 1.30-2.40), reduced global longitudinal strain (reflecting systolic function; OR = 1.68; 95% CI = 1.16-2.44), and greater left atrial volume index (reflecting diastolic function; OR = 1.60; 95% CI = 1.13-2.27), which together demonstrated the greatest association with frailty (OR = 2.10; 95% CI = 1.57-2.82) of the systems studied. Lower magnitude associations were observed for vascular and pulmonary abnormalities, anemia, and impaired renal function. Cardiovascular abnormalities remained associated with frailty after excluding participants with prevalent cardiovascular disease.
Abnormalities of cardiac structure and function are independently associated with frailty, and together show the greatest association with frailty among the organ systems studied.
Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose.
We compared the prognostic value of ...glycated hemoglobin and fasting glucose for identifying adults at risk for diabetes or cardiovascular disease. We measured glycated hemoglobin in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990-1992 period) of the Atherosclerosis Risk in Communities (ARIC) study.
The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable-adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose.
In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes.
Most population-based estimates of incident hospitalized heart failure (HF) have not differentiated acute decompensated heart failure (ADHF) from chronic stable HF nor included racially diverse ...populations. The Atherosclerosis Risk in Communities Study conducted surveillance of hospitalized HF events (age ≥55 years) in 4 US communities. We estimated hospitalized ADHF incidence and survival by race and gender. Potential 2005 to 2009 HF hospitalizations were identified by International Classification of Diseases, Ninth Revision, Clinical Modification , codes; 6,168 records were reviewed to validate ADHF cases. Population estimates were derived from US Census data; 50% of eligible hospitalizations were classified as ADHF, of which 63.6% were incident ADHF and 36.4% were recurrent ADHF. The average incidence of hospitalized ADHF was 11.6 per 1,000 persons, aged ≥55 years, per year, and recurrent hospitalized ADHF was 6.6 per 1,000 persons/yr. Age-adjusted annual ADHF incidence was highest for black men (15.7 per 1,000), followed by black women (13.3 per 1,000), white men (12.3 per 1,000), and white women (9.9 per 1,000). Of incident ADHF events with heart function assessment (89%), 53% had reduced the ejection fraction (heart failure with reduced ejection fraction HFrEF) and 47% had preserved ejection fraction (heart failure with preserved ejection fraction HFpEF). Black men had the highest proportion of acute HFrEF events (70%); white women had the highest proportion of acute HFpEF (59%). Age-adjusted 28-day and 1-year case fatality after an incident ADHF was 10.4% and 29.5%, respectively. Survival did not differ by race or gender. In conclusion, ADHF hospitalization and HF type varied by both race and gender, but case fatality rates did not. Further studies are needed to explain why black men are at higher risk of hospitalized ADHF and HFrEF.
Context:
Metabolomic profiling of amino acids and acylcarnitines has revealed consistent patterns associated with metabolic disease.
Objective:
This study used metabolomic profiling to identify ...analytes associated with insulin sensitivity (SI) and conversion to type 2 diabetes (T2D).
Design:
A multiethnic cohort from the Insulin Resistance Atherosclerosis Study.
Setting:
Community-based.
Patients:
A total of 196 subjects (European American, Hispanic, and African American) were selected to represent extremes of the SI distribution and conversion to T2D between baseline and followup exams.
Main Outcome:
Mass spectrometry–based profiling of 69 metabolites. Subjects participated in a frequently sampled iv glucose tolerance test to measure SI and acute insulin response. T2D status was determined by a 2-hour oral glucose tolerance test.
Results:
Logistic regression analysis from 72 high and 75 low SI subjects revealed significantly decreased glycine and increased valine, leucine, phenylalanine, and combined glutamine and glutamate (P = .0079–7.7 × 10−6) in insulin-resistant subjects. Ethnic-stratified results were strongest in European Americans. Comparing amino acid profiles between subjects that converted to T2D (76 converters; 70 nonconverters) yielded a similar pattern of associations: decreased glycine and increased valine, leucine, and combined glutamine and glutamate (P = .016–.00010). Importantly, β-cell function as a covariate revealed a similar pattern of association.
Conclusions:
A distinct pattern of differences in amino acids were observed when comparing subjects with high and low levels of SI. This pattern was associated with conversion to T2D, remaining significant when accounting for β-cell function, emphasizing a link between this metabolic profile and insulin resistance. These results demonstrate a consistent metabolic signature associated with insulin resistance and conversion to T2D, providing potential insight into underlying mechanisms of disease pathogenesis.
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