Lewis H Kuller

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (745)5012.58 Total impact

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    ABSTRACT: Alzheimer disease is the most common form of dementia in the elderly, and the complex relationships among risk factors produce highly variable natural histories from normal cognition through the prodromal stage of mild cognitive impairment (MCI) to clinical dementia. We used a novel statistical approach, mixed membership trajectory models, to capture the variety of such pathways in 652 participants in the Cardiovascular Health Study Cognition Study over 22 years of follow-up (1992-2014). We identified 3 trajectories: a "healthy" profile with a peak probability of MCI between 95 and 100 years of age and only a 50% probability of dementia by age 100; an "intermediate" profile with a peak probability of MCI between 85 and 90 years of age and progression to dementia between 90 and 95 years; and an "unhealthy" profile with a peak probability of progressing to MCI between ages 75 and 80 years and to dementia between the ages of 80 and 85 years. Hypertension, education, race, and the ϵ4 allele of the apolipoprotein E gene all affected the closeness of an individual to 1 or more of the canonical trajectories. These results provide new insights into the natural history of Alzheimer disease and evidence for a potential difference in the pathophysiology of the development of dementia. © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    American journal of epidemiology 07/2015; 182(4). DOI:10.1093/aje/kwv051 · 5.23 Impact Factor
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    ABSTRACT: The Seven Countries Study in the 1960s showed very low mortality from coronary heart disease (CHD) in Japan, which was attributed to very low levels of total cholesterol. Studies of migrant Japanese to the USA in the 1970s documented increase in CHD rates, thus CHD mortality in Japan was expected to increase as their lifestyle became Westernized, yet CHD mortality has continued to decline since 1970. This study describes trends in CHD mortality and its risk factors since 1980 in Japan, contrasting those in other selected developed countries. We selected Australia, Canada, France, Japan, Spain, Sweden, the UK and the USA. CHD mortality between 1980 and 2007 was obtained from WHO Statistical Information System. National data on traditional risk factors during the same period were obtained from literature and national surveys. Age-adjusted CHD mortality continuously declined between 1980 and 2007 in all these countries. The decline was accompanied by a constant fall in total cholesterol except Japan where total cholesterol continuously rose. In the birth cohort of individuals currently aged 50-69 years, levels of total cholesterol have been higher in Japan than in the USA, yet CHD mortality in Japan remained the lowest: > 67% lower in men and > 75% lower in women compared with the USA. The direction and magnitude of changes in other risk factors were generally similar between Japan and the other countries. Decline in CHD mortality despite a continuous rise in total cholesterol is unique. The observation may suggest some protective factors unique to Japanese. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
    International Journal of Epidemiology 07/2015; DOI:10.1093/ije/dyv143 · 9.18 Impact Factor
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    ABSTRACT: The literature on environment and obesity is characterized by studies that are often cross-sectional and lack racial diversity. This study examined associations between neighborhood features and BMI development over 6 years in an urban sample of 2,295 girls (56% African American; mean age at baseline, 11.2 years) in 2004. Analyses were conducted in 2011-2015. Girls, caregivers, and study staff completed annual neighborhood questionnaires. Linear mixed-effects modeling examined annual changes in neighborhood features and BMI and assessed whether baseline neighborhood features modified BMI growth over time. At baseline, 40% of participants were overweight/obese. Participants' neighborhoods had few neighborhood problems, moderate levels of safety issues and inconvenient features, low levels of neighborhood disorder, few cases of loitering youth, and substantial traffic volume. Adverse neighborhood features were more common for African American than white participants. Neighborhood features were relatively stable over the follow-up period. African American girls with helpful neighbors had lower annual BMI growth (-0.09 kg/m(2)) than others. For white girls, BMI increased more for girls with helpful neighbors (+0.09 kg/m(2) annually). Regardless of race, living in a U.S. Census tract with low levels of educational achievement was linked with higher BMI growth (an additional 0.07 kg/m(2) annually). Girls living in Census tracts with high (versus low) levels of poverty gained an additional 0.08 kg/m(2) gain annually. Social environment features are associated with BMI change in white and African American urban girls and may be helpful for identifying girls at risk for early adolescent weight gain. Copyright © 2015 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.
    American journal of preventive medicine 07/2015; DOI:10.1016/j.amepre.2015.05.021 · 4.53 Impact Factor
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    ABSTRACT: The prevalence of cardiometabolic multimorbidity is increasing. To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). All-cause mortality and estimated reductions in life expectancy. In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
    JAMA The Journal of the American Medical Association 07/2015; 314(1):52-60. DOI:10.1001/jama.2015.7008 · 35.29 Impact Factor
  • Rachel H. Mackey · Lewis H. Kuller
    Journal of the American College of Cardiology 06/2015; 65(23). DOI:10.1016/j.jacc.2015.03.574 · 16.50 Impact Factor
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    ABSTRACT: To understand the incidence and persistence of severe obesity (>1.2x 95th BMI percentile-for-age) in girls across the transition to adolescence, and map developmental trajectories of adolescent severe obesity in a high-risk sample.
    Journal of Clinical and Translational Endocrinology 06/2015; DOI:10.1016/j.jcte.2015.04.001
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    ABSTRACT: This report evaluates incidence of cardiovascular disease (CVD) morbidity and mortality over 10 years among the >160,000 postmenopausal women in the Women's Health Initiative (WHI) in relation to self-reported RA, disease modifying anti-rheumatic drugs (DMARD) use, anti-CCP+, RF+, CVD risk factors, joint pain, and inflammation (white blood cell (WBC) count and IL-6.) Methods: Anti-CCP and RF were measured on a sample (n=9,988) of WHI participants with self-reported RA. RA was classified as self-reported RA plus anti-CCP+ positivity and/or use of DMARDs. Self-reported RA that was both anti-CCP- and DMARD- was classified as "unverified RA." Age-adjusted rates of coronary heart disease (CHD), stroke, CVD, fatal CVD and total mortality were higher for women with RA vs. no RA, with multivariable-adjusted HR(95%CI) of 1.46(1.17, 1.83) for CHD, and 2.55(1.86, 3.51) for fatal CVD. Within RA, anti-CCP+ and RF+ were not significantly associated with higher risk of any outcomes, despite slightly higher risk of fatal CVD and death for anti-CCP+ vs. anti-CCP- RA. Joint pain severity and CVD risk factors were strongly associated with CVD risk, even for women with no RA. CVD incidence was increased for RA vs. no RA at almost all risk factor levels, except low levels of joint pain or inflammation. Within RA, inflammation was more strongly associated with fatal CVD and total mortality than CHD or CVD. Among postmenopausal women, RA was associated with 1.5-2.5 higher CVD risk, strongly associated with CV risk factors, joint pain severity, and inflammation, but similar for anti-CCP+ and RF+. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
    Arthritis and Rheumatology 05/2015; 67(9). DOI:10.1002/art.39198
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    ABSTRACT: Given conflicting data regarding the association of HIV infection and ischemic stroke risk, we sought to determine whether HIV infection conferred an increased ischemic stroke risk among male veterans. The Veterans Aging Cohort Study-Virtual Cohort consists of HIV-infected and uninfected veterans in care matched (1:2) for age, sex, race/ethnicity, and clinical site. We analyzed data on 76,835 male participants in the Veterans Aging Cohort Study-Virtual Cohort who were free of baseline cardiovascular disease. We assessed demographics, ischemic stroke risk factors, comorbid diseases, substance use, HIV biomarkers, and incidence of ischemic stroke from October 1, 2003, to December 31, 2009. During a median follow-up period of 5.9 (interquartile range 3.5-6.6) years, there were 910 stroke events (37.4% HIV-infected). Ischemic stroke rates per 1,000 person-years were higher for HIV-infected (2.79, 95% confidence interval 2.51-3.10) than for uninfected veterans (2.24 [2.06-2.43]) (incidence rate ratio 1.25 [1.09-1.43]; p < 0.01). After adjusting for demographics, ischemic stroke risk factors, comorbid diseases, and substance use, the risk of ischemic stroke was higher among male veterans with HIV infection compared with uninfected veterans (hazard ratio 1.17 [1.01-1.36]; p = 0.04). HIV infection is associated with an increased ischemic stroke risk among HIV-infected compared with demographically and behaviorally similar uninfected male veterans. © 2015 American Academy of Neurology.
    Neurology 04/2015; 84(19). DOI:10.1212/WNL.0000000000001560 · 8.29 Impact Factor
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    ABSTRACT: Brachial-ankle pulse wave velocity (baPWV) is a simple and reproducible measure of arterial stiffness and is extensively used to assess cardiovascular disease (CVD) risk in eastern Asia. We examined whether baPWV is associated with coronary atherosclerosis in an international study of healthy middle-aged men. A population-based sample of 1131 men aged 40-49years was recruited - 257 Whites and 75 Blacks in Pittsburgh, US, 228 Japanese-Americans in Honolulu, US, 292 Japanese in Otsu, Japan, and 279 Koreans in Ansan, Korea. baPWV was measured with an automated waveform analyzer (VP2000, Omron) and atherosclerosis was examined as coronary artery calcification (CAC) by computed-tomography (GE-Imatron EBT scanner). Association of the presence of CAC (defined as ≥10Agatston unit) was examined with continuous measure as well as with increasing quartiles of baPWV. As compared to the lowest quartile of baPWV, the multivariable-adjusted odds ratio (95% Confidence Interval [CI]) for the presence of CAC in the combined sample was 1.70 (0.98, 2.94) for 2nd quartile, 1.88 (1.08, 3.28) for 3rd quartile, and 2.16 (1.19, 3.94) for 4th quartile (p-trend=0.01). The odds for CAC increased by 19% per 100cm/s increase (p<0.01), or by 36% per standard-deviation increase (p<0.01) in baPWV. Similar effect-sizes were observed in individual races, and were significant among Whites, Blacks and Koreans. baPWV is cross-sectionally associated with CAC among healthy middle-aged men. The association was significant in Whites and Blacks in the US, and among Koreans. Longitudinal studies are needed to determine its CVD predictive ability. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 04/2015; 189(1):67-72. DOI:10.1016/j.ijcard.2015.04.020 · 4.04 Impact Factor
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    ABSTRACT: We hypothesized that higher concentrations of LDL particles (LDL-P) and leptin, and lower concentrations of HDL particles (HDL-P), and total and high molecular weight (HMW) adiponectin, would predict incident coronary heart disease (CHD) among severely obese postmenopausal women. In a case-cohort study nested in the Women's Health Initiative Observational Study, we sampled 677 of the 1852 white or black women with body mass index (BMI) ≥40 kg/m(2) and no prevalent cardiovascular disease (CVD), including all 124 cases of incident CHD over mean 5.0 year follow-up. Biomarkers were assayed on stored blood samples. In multivariable-adjusted weighted Cox models, higher baseline levels of total and small LDL-P, and lower levels of total and medium HDL-P, and smaller mean HDL-P size were significantly associated with incident CHD. In contrast, large HDL-P levels were inversely associated with CHD only for women without diabetes, and higher total and HMW adiponectin levels and lower leptin levels were associated with CHD only for women with diabetes. Higher total LDL-P and lower HDL-P were associated with CHD risk independently of confounders including CV risk factors and other lipoprotein measures, with adjusted HR (95%CIs) of 1.55(1.28, 1.88) and (0.70 (0.57, 0.85), respectively, and similar results for medium HDL-P. Higher CHD risk among severely obese postmenopausal women is strongly associated with modifiable concentrations of LDL-P and HDL-P, independent of diabetes, smoking, hypertension, physical activity, BMI and waist circumference. Severely obese postmenopausal women should be considered high risk candidates for lipid lowering therapy.
    Biochimica et Biophysica Acta - Clinical 03/2015; 120. DOI:10.1016/j.bbacli.2015.03.005
  • Akira Sekikawa · Margaret F Doyle · Lewis H Kuller
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    ABSTRACT: Recent long-term randomized clinical trials (RCTs) of long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFAs) on coronary heart disease (CHD) among high-risk patients conducted in Western countries all failed to show their clinical benefits. In striking contrast, an RCT of LCn-3 PUFAs on CHD conducted in Japan, which is a combination of secondary and primary prevention, showed a significant 19% reduction. Potential reasons for this discrepancy are large differences in doses of LCn-3 PUFAs administered (300-900mg/day in Western countries vs. 1800 mg/day in Japan) and background dietary intake of LCn-3 PUFAs (<300mg/day in Western countries vs. >1000mg/day in Japan). These observations suggest that higher doses of LCn-3 PUFAs than examined in RCTs in Western countries may be cardio-protective. Atherosclerosis is the major underlying cause of CHD. Recent observational studies and an RCT of LCn-3 PUFAs on atherosclerosis in Japan show that LCn-3 PUFAs are anti-atherogenic. In this brief review, we focus on recent epidemiological and clinical findings of LCn-3 PUFAs on atherosclerosis and CHD, contrasting studies in Western countries to those in Japan. We also discuss mechanisms of high-dose LCn-3 PUFAs on atherosclerosis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Trends in cardiovascular medicine 03/2015; DOI:10.1016/j.tcm.2015.03.001 · 2.91 Impact Factor
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    ABSTRACT: The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer's disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study-Cognition Study (mean age = 79.2 ± 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p < 0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5 × 10-8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person's increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.
    Journal of Alzheimer's disease: JAD 02/2015; 46(1). DOI:10.3233/JAD-150047 · 4.15 Impact Factor
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    ABSTRACT: We study regularized estimation in high-dimensional longitudinal classification problems, using the lasso and fused lasso regularizers. The constructed coefficient estimates are piecewise constant across the time dimension in the longitudinal problem, with adaptively selected change points (break points). We present an efficient algorithm for computing such estimates, based on proximal gradient descent. We apply our proposed technique to a longitudinal data set on Alzheimer's disease from the Cardiovascular Health Study Cognition Study, and use this data set to motivate and demonstrate several practical considerations such as the selection of tuning parameters, and the assessment of model stability.
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    ABSTRACT: Human Immunodeficiency Virus- (HIV-) infected persons have a higher risk for acute myocardial infarction (AMI) than HIV-uninfected persons. Earlier studies suggest that HIV viral load, CD4(+) T-cell count, and antiretroviral therapy are associated with cardiovascular disease (CVD) risk. Whether CD8(+) T-cell count is associated with CVD risk is not clear. We investigated the association between CD8(+) T-cell count and incident AMI in a cohort of 73,398 people (of which 97.3% were men) enrolled in the U.S. Veterans Aging Cohort Study-Virtual Cohort (VACS-VC). Compared to uninfected people, HIV-infected people with high baseline CD8(+) T-cell counts (>1065 cells/mm(3)) had increased AMI risk (adjusted HR = 1.82, P < 0.001, 95% CI: 1.46 to 2.28). There was evidence that the effect of CD8(+) T-cell tertiles on AMI risk differed by CD4(+) T-cell level: compared to uninfected people, HIV-infected people with CD4(+) T-cell counts ≥200 cells/mm(3) had increased AMI risk with high CD8(+) T-cell count, while those with CD4(+) T-cell counts <200 cells/mm(3) had increased AMI risk with low CD8(+) T-cell count. CD8(+) T-cell counts may add additional AMI risk stratification information beyond that provided by CD4(+) T-cell counts alone.
    BioMed Research International 01/2015; 2015:246870. DOI:10.1155/2015/246870 · 3.17 Impact Factor
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    ABSTRACT: Aim: To examine whether the inflammatory markers C-reactive protein (CRP) and fibrinogen are associated with biomarkers of atherosclerosis [carotid intima-media thickness (IMT) and coronary artery calcification (CAC)] in the general male population, including Asians. Methods: Population-based samples of 310 Japanese, 293 Japanese-American and 297 white men 40-49 years of age without clinical cardiovascular disease underwent measurement of IMT, CAC and the CRP and fibrinogen levels as well as other conventional risk factors using standardized methods. Statistical associations between the variables were evaluated using multiple linear or logistic regression models. Results: The Japanese group had significantly lower levels of inflammatory markers and subclinical atherosclerosis than the Japanese-American and white groups (P-values all <0.001). The mean level of CRP was 0.66 vs. 1.11 and 1.47 mg/L, while that of fibrinogen was 255.0 vs. 313.0 and 291.5 mg/dl, respectively. In addition, the mean carotid IMT was 0.61 vs. 0.73 and 0.68 mm, while the mean prevalence of CAC was 11.6% vs. 32.1% and 26.3%, respectively. Body mass index (BMI) showed significant positive associations with both the CRP and fibrinogen levels. Although CRP showed a significant positive association with IMT in the Japanese men, this association became non-significant following adjustment for traditional risk factors or BMI. In all three populations, CRP was not found to be significantly associated with the prevalence of CAC. Similarly, fibrinogen did not exhibit a significant association with either IMT or the prevalence of CAC. Conclusions: The associations between inflammatory markers and subclinical atherosclerosis may merely reflect the strong associations between BMI and the levels of inflammatory markers and incidence of subclinical atherosclerosis in both Eastern and Western populations.
    Journal of atherosclerosis and thrombosis 11/2014; 22(6). DOI:10.5551/jat.23580 · 2.73 Impact Factor
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    ABSTRACT: Aims/hypothesis: At the same level of BMI, white people have less visceral adipose tissue (VAT) and are less susceptible to developing type 2 diabetes than Japanese people. No previous population-based studies have compared insulin resistance and insulin secretion between these two races in a standardised manner that accounts for VAT. We compared HOMA-IR, HOMA of beta cell function (HOMA-β%) and disposition index (DI) in US white men and Japanese men in Japan. Methods: We conducted a population-based, cross-sectional study, comprising 298 white men and 294 Japanese men aged 40-49 years without diabetes. Insulin, glucose, VAT and other measurements were performed at the University of Pittsburgh. We used ANCOVA to compare geometric means of HOMA-IR, HOMA-β% and DI, adjusting for VAT and other covariates. Results: White men had higher HOMA-IR, HOMA-β% and DI than Japanese men, and the difference remained significant (p < 0.01) after adjusting for VAT (geometric mean [95% CI]): 3.1 (2.9, 3.2) vs 2.5 (2.4, 2.6), 130.8 (124.6, 137.3) vs 86.7 (82.5, 91.0), and 42.4 (41.0, 44.0) vs 34.8 (33.6, 36.0), respectively. Moreover, HOMA-IR, HOMA-β% and DI were significantly higher in white men even after further adjustment for BMI, impaired fasting glucose and other risk factors. Conclusions/interpretation: The higher VAT-adjusted DI in white men than Japanese men may partly explain lower susceptibility of white people than Japanese people to developing type 2 diabetes. The results, however, should be interpreted with caution because the assessment of insulin indices was made using fasting samples and adjustment was not made for baseline glucose tolerance. Further studies using formal methods to evaluate insulin indices are warranted.
    Diabetologia 10/2014; 58(2). DOI:10.1007/s00125-014-3414-6 · 6.67 Impact Factor
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    ABSTRACT: Objective: To examine the association between brain structural changes and β-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later. Methods: Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011. Results: At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB+, had small hippocampal volume (<25th percentile), or had high white matter lesion (WML) volume (>75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB+. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB+, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores. Conclusions: The prevalence of β-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia.
    Neurology 10/2014; 83(20). DOI:10.1212/WNL.0000000000000977 · 8.29 Impact Factor
  • Lewis H. Kuller · Oscar L. Lopez
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    ABSTRACT: Cardiovascular disease (CVD) contributes to risk of dementia by either enhancing the development and progression of brain vascular disease and subsequent neurodegeneration and Alzheimer's disease (AD) pathology, ie, amyloid plaques and neurofibrillary tangles, acts as a precipitant of dementia in older individuals with preexisting subclinical neuropathology of dementia. Atrial fibrillation, congestive heart failure (CHF), stroke, and myocardial infarction are associated with increased risk of dementia. All older individuals age 65–70+ can be considered to be at very high risk of vascular disease and dementia and candidates for aggressive CV preventive therapies, such as lipid lowering, antihypertensive therapy, increased physical activity, antidiabetic therapies, smoking cessation, etc to prevent heart attacks subsequent CHF, atrial fibrillation, stroke, frailty, and dementia. Furthermore, preventing or delaying dementia should be a primary outcome of all CV trials in older individuals.
    Current Cardiovascular Risk Reports 10/2014; 8(10). DOI:10.1007/s12170-014-0401-x
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    ABSTRACT: Background: The Women's Health Initiative (WHI) low fat (20% kcal) diet modification (DM) trial (1993-2005) demonstrated a non-significant reduction in breast cancer, a nominally significant reduction in ovarian cancer and no effect on other cancers (mean 8.3 years intervention). Consent to non-intervention follow-up was 83% (n=37,858). This analysis was designed to assess post-intervention cancer risk in women randomized to the low-fat diet (40%) versus usual diet comparison (60%). Methods: Randomized, controlled low fat diet intervention for prevention of breast and colorectal cancers conducted in 48,835 postmenopausal U.S. women, aged 50-79 years at 40 U.S. sites. Outcomes included total invasive cancer, breast and colorectal cancer, cancer-specific and overall mortality. Results: There were no intervention effects on invasive breast 1.08 (0.94, 1.24) or colorectal cancer, other cancers, cancer-specific or overall mortality during the post-intervention period or the combined intervention and follow-up periods. For invasive breast cancer, the HRs were 0.92 (0.84, 1.01) during intervention, during the post-intervention period, and 0.97 (0.89, 1.05) during cumulative follow up. A reduced risk for estrogen receptor positive/progesterone receptor negative tumors was demonstrated during follow-up. Women with higher baseline fat intake (quartile), point estimates of breast cancer risk were HR-0.76; 0.62, 0.92 during intervention versus HR-1.11; 0.84, 1.4 during post-intervention follow-up (p-diff=.03). Conclusions: Dietary fat intake rose post-intervention in intervention women; no long-term reduction in cancer risk or mortality was shown in the WHI DM trial. Impact: Dietary advisement to reduce fat for cancer prevention after menopause generally was not supported by the WHI DM trial.
    Cancer Epidemiology Biomarkers & Prevention 09/2014; 23(12). DOI:10.1158/1055-9965.EPI-14-0922 · 4.13 Impact Factor
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    ABSTRACT: There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired β-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic β-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.
    PLoS ONE 09/2014; 9(9):e106537. DOI:10.1371/journal.pone.0106537 · 3.23 Impact Factor

Publication Stats

38k Citations
5,012.58 Total Impact Points


  • 1975–2015
    • University of Pittsburgh
      • • Graduate School of Public Health
      • • Department of Epidemiology
      • • Department of Medicine
      • • Department of Neurological Surgery
      • • Department of Psychiatry
      Pittsburgh, Pennsylvania, United States
  • 2013
    • Wake Forest University
      • Department of Internal Medicine
      Winston-Salem, North Carolina, United States
  • 2012
    • Northwestern University
      Evanston, Illinois, United States
  • 2011
    • Weill Cornell Medical College
      • Department of Medicine
      New York, New York, United States
  • 1994–2011
    • Fred Hutchinson Cancer Research Center
      • Division of Public Health Sciences
      Seattle, Washington, United States
    • University of Benin
      Benim, Edo, Nigeria
    • University of Alabama at Birmingham
      • Department of Medicine
      Birmingham, AL, United States
    • University of Melbourne
      • Department of Ophthalmology
      Melbourne, Victoria, Australia
  • 2010
    • Medical University of South Carolina
      • Department of Medicine
      Charleston, South Carolina, United States
  • 1998–2010
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1999–2009
    • University of Vermont
      • Department of Pathology
      Burlington, VT, United States
    • North Carolina Department of Health and Human Services
      Raleigh, North Carolina, United States
  • 2007
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • University of California, Davis
      • Center for Neuroscience
      Davis, CA, United States
    • University of California, Los Angeles
      • Department of Epidemiology
      Los Angeles, CA, United States
  • 2003–2007
    • University of Helsinki
      • Department of Psychology
      Helsinki, Province of Southern Finland, Finland
    • San Diego State University
      San Diego, California, United States
    • Beth Israel Deaconess Medical Center
      • Division of General Medicine and Primary Care
      Boston, MA, United States
  • 2006
    • University at Buffalo, The State University of New York
      • Department of Social and Preventive Medicine
      Buffalo, NY, United States
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2004–2006
    • Johns Hopkins University
      • Department of Mental Health
      Baltimore, Maryland, United States
    • Saint Louis University
      Сент-Луис, Michigan, United States
    • New England Baptist Hospital
      Boston, Massachusetts, United States
  • 2005
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 2000–2004
    • University of Washington Seattle
      • Department of Medicine
      Seattle, Washington, United States
    • University of California, San Francisco
      San Francisco, California, United States
  • 1991–1997
    • Western Psychiatric Institute and Clinic
      Pittsburgh, Pennsylvania, United States
  • 1996
    • University of Benin Teaching Hospital
      Benim, Edo, Nigeria
  • 1995
    • Graduate School USA
      Washington, Washington, D.C., United States
  • 1989–1992
    • Childrens Hospital of Pittsburgh
      • Department of Pediatrics
      Pittsburgh, Pennsylvania, United States
  • 1988
    • Pennsylvania Department of Health
      Harrisburg, Pennsylvania, United States
  • 1986
    • Georgia Health Sciences University
      • Department of Medicine
      Augusta, Georgia, United States
  • 1984
    • Rutgers New Jersey Medical School
      • Department of Medicine
      Newark, New Jersey, United States