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1.  Dietary Fats, Cholesterol and Iron as Risk Factors for Parkinson's Disease 
Epidemiologic findings suggest that dietary components may contribute to the etiology of Parkinson's disease (PD). This population-based case-control study evaluated PD risk and dietary intake of fats, cholesterol and iron.
Newly diagnosed case (n = 420) and age/gender/ethnicity-matched unrelated controls (n = 560) were identified between 1992 and 2006 from the Group Health Cooperative health maintenance organization in western Washington State, and the University of Washington neurology clinic. In-person interviews elicited data on food frequency habits during most of adult life. Nutritional intakes were calculated and analyzed, with adjustments made for total energy intake (the ‘nutrition density’ technique).
Cholesterol intake in the highest quartile compared with the lowest quartile was associated with a decreased risk of PD in men (odds ratio (OR)=0.53, 95% CI: 0.33, 0.86). The highest versus the lowest quartile of dietary iron increased PD risk in men (OR=1.82, 95% CI: 1.11, 2.99). When the lowest quartile of cholesterol and the highest quartile for iron were compared to the highest quartile of cholesterol and the lowest quartile of iron, no association was seen in women, but for men PD risk was increased (OR=2.70, 95% CI: 1.26, 5.76). Saturated fat intake below the median in combination with iron intake above the median also increased PD risk (OR=1.50, 95% CI: 1.07, 2.11) in both genders combined.
A low intake of cholesterol, particularly in the presence of high iron, may be associated with an increased risk for PD.
PMCID: PMC2751763  PMID: 18424169
2.  Gene Variants Associated With Ischemic Stroke 
Background and Purpose
The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke.
Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS).
In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS.
The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.
PMCID: PMC2881155  PMID: 19023099
brain infarction; cerebrovascular accident; epidemiology; genetics; prevention; risk factors
3.  Parkinson's disease and history of outdoor occupation 
Parkinsonism & related disorders  2013;19(12):1164-1166.
Human and animal studies, albeit not fully consistent, suggest that vitamin D may reduce risk of Parkinson's disease (PD). Ultraviolet radiation converts vitamin D precursor to the active form. This study examined the hypothesis that working outdoors is associated with a decreased risk of PD.
PD cases were enrolled from Group Health Cooperative, a health maintenance organization in the Puget Sound region in western Washington State, and the University of Washington Neurology Clinic in Seattle. Participants included 447 non-Hispanic Caucasian newly diagnosed PD cases diagnosed between 1992 and 2008 and 578 unrelated neurologically normal controls enrolled in Group Health Cooperative, frequency matched by race/ethnicity, age and gender. Subjects' amount of outdoor work was estimated from self-reported occupational histories. Jobs were categorized by degree of time spent working outdoors. A ten-year lag interval was included to account for disease latency. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression, with adjustment for age, gender, and smoking.
Outdoor work was inversely associated with risk of PD (outdoor only compared to indoor only): OR= 0.74, 95% CI 0.44-1.25. However, there was no trend in relation to portion of the workday spent laboring outdoors and PD risk.
Occupational sunlight exposure and other correlates of outdoor work is not likely to have a substantial role in the etiology of PD.
PMCID: PMC3927788  PMID: 24044947
Parkinson's disease; occupation; ultraviolet radiation; vitamin D
4.  LINE-1 DNA Methylation, Smoking and Risk of Parkinson’s Disease 
Journal of Parkinson's disease  2012;2(4):303-308.
Long interspersed nucleotide element-1 (LINE-1) retrotransposons are located throughout the human genome. Those retaining an intact 5′ promoter can copy and insert themselves into the DNA of neural progenitor cells that express tyrosine hydroxylase, which may influence differentiation and survival of these cells. Because LINE-1 promoter methylation is associated with decreased LINE-1 propagation, we compared LINE-1 methylation profiles in blood mononuclear cells between 292 newly diagnosed Parkinson’s disease (PD) cases and 401 unrelated, neurologically normal controls. Overall, PD was not associated with percent methylation of the LINE-1 promoter. However, the predictable inverse association between PD and ever smoking tobacco was strongest for men and women with the lowest LINE-1 promoter methylation, and less apparent as LINE-1 methylation increased. Underlying this possible interaction, ever regularly smoking tobacco was associated with decreased LINE-1 methylation in controls (age- and sex-adjusted linear regression β = −0.24, 95% confidence interval [CI] −0.43, −0.04), but not in cases (β = 0.06, 95% CI −0.17, 0.28, interaction p = 0.06). PD cases may have innate differences in their ability to respond to tobacco smoke.
PMCID: PMC3962286  PMID: 23938260
5.  Occupational Factors and Risk of Parkinson’s Disease: A Population-Based Case–Control Study 
Parkinson’s disease (PD) has been associated with various workplace factors, but the evidence is inconsistent.
To estimate the risk of PD associated with various jobs and workplace exposures.
We conducted a population-based, case–control study of 404 incident PD cases and 526 age and sex-matched controls, collecting self-reported work histories including job titles and exposures to various industrial toxicants. Relative risks of PD from these exposures were estimated with odds ratios (OR) and 95% confidence intervals (CI) using logistic regression.
Risk was not significantly affected by farming work, by metal work, or by exposure to pesticides, metals, or solvents.
These findings do not provide support for the hypothesis that workplace factors affect the risk of PD.
PMCID: PMC3299410  PMID: 20025075
risk factors in epidemiology; Parkinson’s disease/parkinsonism; toxicology; occupational; human
6.  Albuminuria and the risk of incident stroke and stroke types in older adults(e–Pub ahead of print) 
Neurology  2010;75(15):1343-1350.
The kidney biomarker that best reflects risk of stroke is unknown. We sought to evaluate the association of stroke with 3 kidney biomarkers: albuminuria, cystatin C, and glomerular filtration rate.
These 3 biomarkers were determined in 3,287 participants without history of stroke from the Cardiovascular Health Study, a longitudinal cohort study of men and women age 65 years and older from 4 US communities. The biomarkers were albuminuria ascertained using urinary albumin-to-creatinine ratio (UACR) from morning spot urine, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C. Outcomes were incident stroke (any, ischemic, or hemorrhagic) during follow-up between 1996 and 2006.
A total of 390 participants had an incident stroke: 81% ischemic, 12% hemorrhagic, and 7% unclassified. In adjusted Cox regression models, UACR was more strongly related to any stroke, ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C. The hazard ratio (HR) of any stroke comparing the top to bottom quintile of UACR was 2.10 (95% confidence interval [CI] 1.47-3.00), while HR for eGFR was 1.29 (95% CI 0.91-1.84) and for cystatin C was 1.22 (95% CI 0.85-1.74). When considering clinically relevant categories, elevated UACR was associated with increased hazard of any stroke and ischemic stroke regardless of eGFR or cystatin C categories.
UACR was the kidney biomarker most strongly associated with risk of incident stroke. Results in this elderly cohort may not be applicable to younger populations. These findings suggest that measures of glomerular filtration and permeability have differential effects on stroke risk.
= atrial fibrillation;
= Cardiovascular Health Study;
= confidence interval;
= estimated glomerular filtration rate;
= hazard ratio;
= left ventricular hypertrophy;
= urinary albumin-to-creatinine ratio.
PMCID: PMC3013484  PMID: 20810996
7.  Acute Kidney Injury is Associated with Increased Hospital Mortality after Stroke 
Acute kidney injury (AKI) is common and associates with poor clinical outcomes. Information about the incidence of AKI and effect on stroke outcomes is limited.
Data were analyzed from a registry of subjects with ischemic stroke and intracerebral hemorrhage (ICH) hospitalized at a single academic medical center. Admission creatinine was considered to be the baseline. AKI was defined as a creatinine increase of 0.3 mg/dL or a percentage increase of at least 50% from baseline, occurring during hospitalization. Multivariate logistic regression models were created for both stroke types, with hospital mortality as the outcome. Covariates included gender, race, age, admission creatinine, admission NIH Stroke Scale score, performance of contrast-enhanced CT scan of the head and neck, and medical co-morbidities.
There were 528 cases of ischemic stroke with 70 deaths (13%), and 829 cases of ICH with 268 deaths (32%). The mean age was 64 years, with 56% men and 71% whites. AKI complicated 14% of ischemic stroke and 21% of ICH hospitalizations. In multivariate analysis stratified by stroke type, AKI was associated with increased hospital mortality from ischemic stroke (odds ratio (OR) 3.08, 95% confidence interval (CI) [1.49–6.35]) but not ICH (OR 0.82, 95% CI [0.50–1.35]), except for those surviving at least two days (OR 2.11, 95% CI [1.18–3.77]).
AKI occurs frequently after stroke and is associated with increased hospital mortality. Further studies are needed to establish if the association is causal and if measures to prevent AKI would result in decreased mortality.
PMCID: PMC3507321  PMID: 22818389
8.  Association of Cardiac Annular / Valvular Calcification with Brain Findings on Magnetic Resonance Imaging in Community Dwelling Older Adults: the Cardiovascular Health Study 
The objective of this study is to investigate the association of mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVSc) with covert magnetic resonance imaging (MRI)-defined brain infarcts.
Clinically silent brain infarcts defined by MRI are associated with increased risk of cognitive decline, dementia, and future overt stroke. Left sided cardiac valvular / annular calcifications are suspected as risk factors for clinical ischemic stroke.
2,680 Cardiovascular Health Study participants without clinical history of stroke or transient ischemic attack underwent both brain MRI (1992–93) and echocardiography (1994–95).
The mean age of the participants was 74.5 years ± 4.8 and 39.3% were men. The presence of any annular / valvular calcification (either MAC or AAC or AVSc), MAC alone, or AAC alone were significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, HDL-cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular / valve calcification remained associated with covert brain infarcts [RR 1.24 (95% CI 1.05, 1.47)]. The degree of annular / valvular calcification severity showed a direct relation with the presence of covert MRI findings.
Left-sided cardiac annular / valvular calcification are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening on the progression of annular / valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk of cognitive impairment and future stroke.
PMCID: PMC4104125  PMID: 21596233
Covert Brain Infarcts; Aortic Valve; Mitral Valve; Calcification; Epidemiology
9.  Atrial fibrillation and cognitive decline 
Neurology  2013;81(2):119-125.
We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation.
We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times.
Analyses included 5,150 participants, of whom 552 (10.7%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was −6.4 points (95% confidence interval [CI]: −7.0, −5.9) for participants without a history of atrial fibrillation, but was −10.3 points (95% CI: −11.8, −8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of −3.9 points (95% CI: −5.3, −2.5).
In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation.
PMCID: PMC3770176  PMID: 23739229
10.  Early diagnosis and treatment of obstructive sleep apnea after stroke 
Neurology: Clinical Practice  2013;3(3):192-201.
Sleep-disordered breathing is an increasingly recognized disorder that is particularly prevalent among stroke patients. Obstructive sleep apnea, a form of sleep-disordered breathing, is associated with multiple major stroke risk factors but is also an independent risk factor for stroke. In addition, untreated sleep apnea is associated with poor functional outcome after stroke. Sleep apnea is amenable to treatment and should be considered a modifiable stroke risk factor, though long-term compliance remains a major barrier. A better understanding of the relationship between sleep apnea and stroke may prompt providers to pursue the early diagnosis and treatment of underlying sleep-disordered breathing to both improve the chance of recovery from stroke in the short term and to reduce the risk of recurrent stroke in the long term.
PMCID: PMC3721244  PMID: 23914326
11.  Neighborhood socioeconomic disadvantage and mortality after stroke 
Neurology  2013;80(6):520-527.
Residence in a socioeconomically disadvantaged community is associated with mortality, but the mechanisms are not well understood. We examined whether socioeconomic features of the residential neighborhood contribute to poststroke mortality and whether neighborhood influences are mediated by traditional behavioral and biologic risk factors.
We used data from the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ≥65 years. Residential neighborhood disadvantage was measured using neighborhood socioeconomic status (NSES), a composite of 6 census tract variables representing income, education, employment, and wealth. Multilevel Cox proportional hazard models were constructed to determine the association of NSES to mortality after an incident stroke, adjusted for sociodemographic characteristics, stroke type, and behavioral and biologic risk factors.
Among the 3,834 participants with no prior stroke at baseline, 806 had a stroke over a mean 11.5 years of follow-up, with 168 (20%) deaths 30 days after stroke and 276 (34%) deaths at 1 year. In models adjusted for demographic characteristics, stroke type, and behavioral and biologic risk factors, mortality hazard 1 year after stroke was significantly higher among residents of neighborhoods with the lowest NSES than those in the highest NSES neighborhoods (hazard ratio 1.77, 95% confidence interval 1.17–2.68).
Living in a socioeconomically disadvantaged neighborhood is associated with higher mortality hazard at 1 year following an incident stroke. Further work is needed to understand the structural and social characteristics of neighborhoods that may contribute to mortality in the year after a stroke and the pathways through which these characteristics operate.
PMCID: PMC3589286  PMID: 23284071
12.  Neighborhood Disadvantage and Ischemic Stroke: The Cardiovascular Health Study (CHS) 
Background and Purpose
Neighborhood characteristics may influence the risk of stroke and contribute to socioeconomic disparities in stroke incidence. The objectives of this study were to examine the relationship between neighborhood socioeconomic status (NSES) and incident ischemic stroke and examine potential mediators of these associations.
We analyzed data from 3834 whites and 785 African Americans enrolled in the Cardiovascular Health Study, a multicenter, population-based, longitudinal study of adults ages ≥65 years from four U.S. counties. The primary outcome was adjudicated incident ischemic stroke. NSES was measured using a composite of six census tract variables. Race-stratified multilevel Cox proportional hazard models were constructed, adjusted for sociodemographic, behavioral, and biologic risk factors.
Among whites, in models adjusted for sociodemographic characteristics, stroke hazard was significantly higher among residents of neighborhoods in the lowest compared to the highest NSES quartile (Hazard Ratio [HR] =1.32; 95% CI 1.01-1.72), with greater attenuation of the HR after adjustment for biologic risk factors (HR=1.16; 0.88-1.52) than for behavioral risk factors (HR=1.30; 0.99-1.70). Among African Americans, we found no significant associations between NSES and ischemic stroke.
Higher risk of incident ischemic stroke was observed in the most disadvantaged neighborhoods among whites, but not among African Americans. The relationship between NSES and stroke among whites appears to be mediated more strongly by biologic than behavioral risk factors.
PMCID: PMC3781011  PMID: 21940966
13.  Symptoms and Risk Factors for Stroke in a Community-Based Observational Sample in Viet Nam 
Viet Nam is experiencing a health transition from infectious to chronic disease. Data on cardiovascular diseases, including strokes, are limited.
Data were randomly collected from six communities in Da Nang, Viet Nam, on participant demographics, medical history, blood pressure, anthropometrics and health behavior using World Health Organization (WHO) guidelines. Stroke symptoms were collected by self-report with the standardized Questionnaire for Verifying Stroke Free Status. Multivariate logistic regression was used to identify factors associated with the presence of stroke symptoms.
1,621 adults were examined with a mean age of 52.0 years (± 12.5 years), of which 56.1% were women. 27.3% of the participants were found to have hypertension, 26.2% used tobacco, and 16.1% were overweight. More than two-thirds of the participants with hypertension were unaware of their condition. Almost one fourth of the participants were identified by the questionnaire as previously experiencing at least one stroke symptom. Age, rural residence, and education were associated with the presence of stroke symptoms. Models adjusted for demographics found hypertension, high cholesterol, reported severe chest pain, former smoking, and being overweight to be associated with a higher prevalence of stroke symptoms.
The high frequency of stroke symptoms in Da Nang calls for further evaluation and interventions to reduce hypertension and other risk factors for chronic disease.
PMCID: PMC3607634  PMID: 23538875
stroke; symptoms; Viet Nam; community-based; risk factors
14.  Common variants at 6q22 and 17q21 are associated with intracranial volume 
Nature genetics  2012;44(5):539-544.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10−11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10−12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10−3 for 6q22 and p=1.2*10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.
PMCID: PMC3618290  PMID: 22504418
15.  Birth Order and Narcolepsy Risk Among Genetically Susceptible Individuals: a Population-based Case-control Study 
Sleep Medicine  2012;13(3):310-313.
Birth order may play a role in autoimmune diseases and early childhood infections, both factors implicated in the etiology of narcolepsy. We investigated the association between birth order and narcolepsy risk in a population-based case-control study in which all study subjects were HLA-DQB1*0602 positive.
Subjects were 18-50 years old, residents of King County, Washington, and positive for HLA-DQB1*0602. Birth order was obtained from administered interviews. We used logistic regression to generate odds ratios adjusted for income and African American race.
Analyses included 67 cases (mean age 34.3 [SD=9.1], 70.2% female) and 95 controls (mean age 35.1 [SD=8.8], 58.1% female). Associations for birth order were as follows: First born (cases 38.8% vs. controls 50.2%, OR=1.0; Reference), second born (cases 29.9% vs. controls 32.9%, OR=1.6; 95% CI 0.7, 3.7), third born or higher (cases 31.3% vs. controls 16.8%, OR=2.5; 95% CI 1.0, 6.0). A linear trend was significant (p<0.05). Sibling number, sibling gender, having children, and number of children did not differ significantly between narcolepsy cases and controls.
Narcolepsy risk was significantly associated with higher birth order in this population-based study of genetically susceptible individuals. This finding supports an environmental influence on narcolepsy risk through an autoimmune mechanism, early childhood infections, or both.
PMCID: PMC3288144  PMID: 22281000
Narcolepsy; Birth order; HLA-DQB1*0602; genetics; autoimmune
16.  Markers of Inflammation in Prevalent and Incident Parkinson’s Disease in the Cardiovascular Health Study 
Parkinsonism & related disorders  2011;18(3):274-278.
Studies demonstrate existence of inflammation in prevalent Parkinson’s disease (PD). We assessed associations of baseline levels of inflammatory markers with prevalent PD at baseline (1989) and incident PD identified over 13 years of follow-up of the Cardiovascular Health Study.
Blood samples at baseline were measured for fibrinogen, interleukin-6, tumor necrosis factor–α, C-reactive protein, albumin, and white blood cells. The analysis included 60 prevalent and 154 incident PD cases.
Risk of prevalent PD was significantly higher per doubling of IL-6 among women (odds ratio [OR] = 1.5, 95% confidence interval [CI]: 1.0, 2.4) and WBC among men (OR: 2.4, 95% CI: 1.2, 4.9) in multivariate models. Risk of incident PD was not associated with higher levels of any biomarker after adjusting for age, smoking, African American race, and history of diabetes. Inverse associations with incident PD were observed per doubling of C-reactive protein (OR=0.9; 95% CI: 0.8, 1.0) and of fibrinogen among women (OR=0.4; 95% CI: 0.2, 0.8).
Although inflammation exists in PD, it may not represent an etiologic factor. Our findings suggest the need for larger studies that measure inflammatory markers before PD onset.
PMCID: PMC3288759  PMID: 22119505
albumins; C-reactive protein; inflammation; interleukin-6; odds ratio; Parkinson’s disease; tumor necrosis factor-α
17.  Gender Differences in Tea, Coffee, and Cognitive Decline in the Elderly: The Cardiovascular Health Study 
Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually by an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.
PMCID: PMC3577072  PMID: 21841254
Caffeine; coffee; cognition; tea
18.  Environmental tobacco smoke and Parkinson disease 
Movement Disorders  2011;27(2):293-297.
Parkinson disease is inversely associated with cigarette smoking, but its relation with passive smoking or environmental tobacco smoke exposure is rarely examined.
Within a case-control study we assessed the association between Parkinson disease and living or working with active smokers. Cases were newly diagnosed with idiopathic Parkinson disease (N=154) from western Washington State in 2002–2008. Age- and sex-matched controls (N=173) were neurologically normal and unrelated to cases.
Compared with never active or passive tobacco smokers, we observed similarly reduced Parkinson disease risks for ever passive smokers only (odds ratio=0.34, 95% confidence interval 0.16–0.73) as for ever active smokers (0.35, 0.17–0.73). Among persons whose only tobacco smoke exposure was passive smoking at home, risk was inversely associated with years exposed.
These observations parallel those well-established for active smoking. However, it remains unresolved whether a true protective effect of tobacco smoke, generally detrimental to health, underlies these associations.
PMCID: PMC3289937  PMID: 22095755
Environmental Tobacco Smoke Pollution; Idiopathic Parkinson Disease; Passive Smoking; Smoking
19.  Mid- and Late-Life Obesity: Risk of Dementia in the Cardiovascular Health Cognition Study 
Archives of neurology  2009;66(3):336-342.
To evaluate associations between mid- and late-life obesity and risk of dementia.
Prospective cohort followed 5.4 years from 1992/4 through 1999.
Community-dwelling sample in four US sites recruited from Medicare eligibility files.
2,798 adults without dementia, mean age 74.7 years, 59.1% women, participating in the Cardiovascular Health Cognition Study completing a magnetic resonance image, measured for height and weight at baseline (late-life) and self-reporting weight at age 50 (mid-life). Body mass index (BMI) was calculated at both times.
Main Outcome Measures
Dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) classified by a multidisciplinary committee using standardized criteria.
Classification resulted in 480 persons with incident dementia, 245 with AD (no VaD) and 213 with VaD (with or without AD). In evaluations of mid-life obesity, an increased risk of dementia was found for obese (BMI >30) compared to normal (BMI 20-25) persons adjusted for demographics (HR: 1.39, 95% CI: 1.03-1.87) and for caradiovascularl risk factors (HR: 1.36, 95% CI: 0.94-1.95). The risk estimates reversed in assessments of late-life BMI. Underweight persons (BMI < 20) had an increased risk of dementia (HR: 1.62, 95% CI: 1.02-2.64) while being overweight (BMI 25-30) was not associated (HR: 0.92, 95% CI: 0.72-1.18) and being obese reduced the risk of dementia (HR: 0.63, 95% CI: 0.44-0.91) compared to those with normal BMI.
These results help explain the “obesity paradox” as differences in dementia risk over time are consistent with physical changes in the trajectory toward disability.
PMCID: PMC3513375  PMID: 19273752
20.  Common variants at 12q14 and 12q24 are associated with hippocampal volume 
Bis, Joshua C. | DeCarli, Charles | Smith, Albert Vernon | van der Lijn, Fedde | Crivello, Fabrice | Fornage, Myriam | Debette, Stephanie | Shulman, Joshua M. | Schmidt, Helena | Srikanth, Velandai | Schuur, Maaike | Yu, Lei | Choi, Seung-Hoan | Sigurdsson, Sigurdur | Verhaaren, Benjamin F.J. | DeStefano, Anita L. | Lambert, Jean-Charles | Jack, Clifford R. | Struchalin, Maksim | Stankovich, Jim | Ibrahim-Verbaas, Carla A. | Fleischman, Debra | Zijdenbos, Alex | den Heijer, Tom | Mazoyer, Bernard | Coker, Laura H. | Enzinger, Christian | Danoy, Patrick | Amin, Najaf | Arfanakis, Konstantinos | van Buchem, Mark A. | de Bruijn, Renée F.A.G. | Beiser, Alexa | Dufouil, Carole | Huang, Juebin | Cavalieri, Margherita | Thomson, Russell | Niessen, Wiro J. | Chibnik, Lori B. | Gislason, Gauti K. | Hofman, Albert | Pikula, Aleksandra | Amouyel, Philippe | Freeman, Kevin B. | Phan, Thanh G. | Oostra, Ben A. | Stein, Jason L. | Medland, Sarah E. | Vasquez, Alejandro Arias | Hibar, Derrek P. | Wright, Margaret J. | Franke, Barbara | Martin, Nicholas G. | Thompson, Paul M. | Nalls, Michael A. | Uitterlinden, Andre G. | Au, Rhoda | Elbaz, Alexis | Beare, Richard J. | van Swieten, John C. | Lopez, Oscar | Harris, Tamara B. | Chouraki, Vincent | Breteler, Monique M.B. | De Jager, Philip L. | Becker, James T. | Vernooij, Meike W. | Knopman, David | Fazekas, Franz | Wolf, Philip A. | van der Lugt, Aad | Gudnason, Vilmundur | Longstreth, W.T. | Brown, Mathew A. | Bennett, David A. | van Duijn, Cornelia M. | Mosley, Thomas H. | Schmidt, Reinhold | Tzourio, Christophe | Launer, Lenore J. | Ikram, M. Arfan | Seshadri, Sudha
Nature genetics  2012;44(5):545-551.
Aging is associated with reductions in hippocampal volume (HV) that are accelerated by Alzheimer’s disease and vascular risk factors. Our genome-wide association study of dementia-free persons (n=9,232) identified 46 SNPs at four loci with p-values <4.0×10-7. Two additional samples (n=2,318) replicated associations at 12q24 within MSRB3/WIF1 (discovery + replication, rs17178006; p=5.3×10-11) and at 12q14 near HRK/FBXW8 (rs7294919; p=2.9×10-11). Remaining associations included one 2q24 SNP within DPP4 (rs6741949; p=2.9×10-7) and nine 9p33 SNPs within ASTN2 (rs7852872; p=1.0×10-7) that were also associated with HV (p<0.05) in a third younger, more heterogeneous sample (n=7,794). The ASTN2 SNP was also associated with decline in cognition in a largely independent sample (n=1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8), enzymes targeted by new diabetes medications (DPP4), and neuronal migration (ASTN2), indicating novel genetic influences that influence hippocampal size and possibly the risk of cognitive decline and dementia.
PMCID: PMC3427729  PMID: 22504421
21.  The Risk of Parkinson Disease Associated with Urate in a Community-Based Cohort of Older Adults 
Neuroepidemiology  2011;36(4):223-229.
Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults.
The association of baseline urate (μmol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 μmol/l), middle (300–500 μmol/l), and high (>500 μmol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD.
Women had significantly lower urate concentrations than did men [316.8 μmol/l (SD 88.0) vs. 367.4 μmol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 μmol/l (OR 1.69, 95% CI 1.03–2.78) but not for urate >500 μmol/l (OR 1.55, 95% CI 0.72–3.32) in men. A negative linear term was significant for urate <500 μmol/l, and across the entire range a convex quadratic term was significant.
Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.
PMCID: PMC3124452  PMID: 21677446
Parkinson disease; Risk factors; Oxidative stress; Epidemiology; Uric acid
22.  Genome-wide association studies of cerebral white matter lesion burden: the CHARGE Consortium 
Annals of neurology  2011;69(6):928-939.
White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10−9), rs11869977 (P=5.7×10−9), rs936393 (P=6.8×10−9), rs3744017 (P=7.3×10−9), and rs1055129 (P=4.1×10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample).
This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
PMCID: PMC3122147  PMID: 21681796
23.  Post Hoc Parkinson's Disease: Identifying an Uncommon Disease in the Cardiovascular Health Study 
Neuroepidemiology  2010;35(4):241-249.
Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis.
We used combinations of self-report, International Classification of Diseases − 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD.
We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8–1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26–0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29–0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null.
Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.
PMCID: PMC2978249  PMID: 20881426
Cardiovascular Health Study; Cohort study; Epidemiology; International Classification of Diseases, 9th edition; Smoking; Parkinson's disease
24.  Genome-wide Analysis of Genetic Loci Associated with Alzheimer’s Disease 
Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD).
In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction.
Design, Setting, and Participants
We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls).
Main outcome measure
Alzheimer’s Disease.
We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003).
Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions.
PMCID: PMC2989531  PMID: 20460622
genome-wide association study; genetic epidemiology; genetics; dementia; Alzheimer’s disease; cohort study; meta-analysis; risk
25.  Two Simple Questions to Assess Neurologic Outcomes at Three Months after Out-of-Hospital Cardiac Arrest: Experience from the Public Access Defibrillation Trial 
Resuscitation  2010;81(5):530-533.
Two simple questions have been used to classify neurologic outcome in patients with stroke. Could they be similarly applied to patients with cardiac arrest?
As part of a randomized trial, study personnel interviewed by telephone survivors of out-of-hospital cardiac arrest to assess their outcomes three months after discharge. They asked two simple questions: 1) In the last two weeks, did you require help from another person for your everyday activities? & 2) Do you feel that you have made a complete mental recovery form your heart arrest? Next they administered the Mini-Mental State Examination (MMSE) from the Adult Lifestyles and Function Interview (ALFI) to assess cognition on a scale from 0 to 22 and the Health Utilities Index Mark 3 (HUI3) to assess quality of life on a scale from 0 (death) to 1 (perfect health).
Based on responses to the two simple questions, 32 survivors were classified as dependent (n=5, 16%), independent (n=3, 9%) and full recovery (n=24, 75%). The mean ALFI-MMSE score was 19.1 (standard deviation 5.1), and the mean HUI3 score was 0.76 (standard deviation 0.28). The classification based on the two simple questions was significantly correlated with ALFI-MMSE (p=0.002) and HUI3 (p=0.001). Scores for the HUI3 were missing in 8 survivors.
Neurologic outcomes based on the two simple questions after cardiac arrest can be easily determined, sensibly applied, and readily interpreted. These preliminary findings justify further evaluation of this simple and practical approach to classify neurologic outcome in survivors of cardiac arrest.
PMCID: PMC2856735  PMID: 20172643
heart arrest; out-of-hospital CPR; outcome; quality of life

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