Rachel A Whitmer

Kaiser Permanente, Oakland, California, United States

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Publications (70)287.59 Total impact

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    ABSTRACT: To investigate whether greater cardiorespiratory fitness (CRF) is associated with better cognitive function 25 years later. We studied 2,747 participants in the community-based Coronary Artery Risk Development in Young Adults Study of black and white men and women aged 18 to 30 years at recruitment in 1985-1986 (baseline year 0). Symptom-limited maximal treadmill test durations at years 0 and 20 provided measures of CRF. Cognitive tests at year 25 measured verbal memory (Rey Auditory Verbal Learning Test [RAVLT]), psychomotor speed (Digit Symbol Substitution Test [DSST]), and executive function (Stroop Test). Per minute of baseline CRF, the RAVLT was 0.12 words recalled higher (standard error [SE] = 0.03, p < 0.0001), the DSST was 0.92 digits higher (SE = 0.13, p < 0.0001), and the Stroop Test score was 0.52 lower (better performance, SE = 0.11, p < 0.0001), after accounting for race, sex, age, education, and clinical center. Compared with the lowest quartile of CRF, each cognitive test was 21% to 34% of an SD better in the highest CRF quartile. Further adjustment for lifestyle and clinical measures attenuated coefficients for RAVLT and DSST slightly, while the coefficient predicting the Stroop Test lost more than half its value (p = 0.07). Analysis in the subset of 1,957 participants who also completed the year-20 treadmill test showed that 20-year change in CRF was positively associated only with DSST (p < 0.001). Better verbal memory and faster psychomotor speed at ages 43 to 55 years were clearly associated with better CRF 25 years earlier.
    Neurology 04/2014; · 8.25 Impact Factor
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    ABSTRACT: Studies have linked mid- and late-life cardiovascular risk factors (CVRFs) to cognitive function, yet little is known about CVRF exposure in early adulthood and subsequent cognitive function. In addition, most studies rely on single assessments of CVRFs which may not accurately reflect long-term exposure. We sought to determine the association between cumulative exposure to CVRFs from early to mid-adulthood and cognitive function at mid-life. In a prospective study of 3,381 adults (ages 18 to 30 at baseline) with 25 years of follow-up, we assessed cognitive function at Year 25 (2010-11) with the Digit Symbol Substitution Test (DSST), Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT) analyzed with standardized z-scores. The primary predictor was 25 year cumulative exposure estimated by areas under the curve (AUCs) for resting systolic and diastolic blood pressure (SBP, DBP), fasting blood glucose (FBG), and total cholesterol. Higher cumulative SBP, DBP, and FBG were consistently associated with worse cognition on all three tests. These associations were primarily significant for exposures above recommended guidelines; cognitive test z scores were between 0.06 to 0.30 points less, on average, for each SD increase in risk factor AUC, after adjusting for age, race, gender, and education, p<0.05 for all. Fewer significant associations were observed for cholesterol. Cumulative exposure to CVRFs from early to mid-adulthood, especially above recommended guidelines, was associated with worse cognition in mid-life. The meaning of this association and whether it warrants more aggressive treatment of CVRFs earlier in life requires further investigation.
    Circulation 03/2014; · 15.20 Impact Factor
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    ABSTRACT: Background: Persons with type 2 diabetes are at an increased risk of dementia compared to those without, but the etiology of this increased risk is unclear. Objective: Cerebral microvascular disease may mediate the link between diabetes and dementia. Given the anatomical and physiological similarities between cerebral and retinal microvessels, we examined the longitudinal association between diabetic retinal disease and dementia in patients with type 2 diabetes. Methods: Longitudinal cohort study of 29,961 patients with type 2 diabetes aged ≥60 years. Electronic medical records were used to collect diagnoses and treatment of severe diabetic retinal disease (i.e., diabetic proliferative retinopathy and macular edema) between 1996-1998 and dementia diagnoses for the next ten years (1998-2008). The association between diabetic retinal disease and dementia was evaluated by Cox proportional hazard models adjusted for sociodemographics, as well as diabetes-specific (e.g., diabetes duration, pharmacotherapy, HbA1c, hypoglycemia, hyperglycemia) and vascular (e.g., vascular disease, smoking, body mass index) factors. Results: 2,008 (6.8%) patients had severe diabetic retinal disease at baseline and 5,173 (17.3%) participants were diagnosed with dementia during follow-up. Those with diabetic retinal disease had a 42% increased risk of incident dementia (demographics adjusted Hazards Ratio (HR) = 1.42, 95% Confidence Interval (CI) 1.27, 1.58); further adjustment for diabetes-specific (HR1.29; 95%CI 1.14,1.45) and vascular-related disease conditions (HR 1.35; 95%CI 1.21,1.52) attenuated the relation slightly. Conclusion: Diabetic patients with severe diabetic retinal disease have an increased risk of dementia. This may reflect a causal link between microvascular disease and dementia.
    Journal of Alzheimer's disease: JAD 03/2014; · 4.17 Impact Factor
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    ABSTRACT: Type 2 diabetes is associated with dementia, and also with more slight cognitive decrements. In this Review we discuss trajectories from normal cognition to dementia in people with type 2 diabetes, and explore opportunities for treatment. Slight diabetes-associated cognitive decrements and dementia affect different age groups and show a different evolution. These cognitive entities should therefore not be regarded as a continuum, although their effects might be additive. Vascular damage is a key underlying process in both entities. Glucose-mediated processes and other metabolic disturbances might also have a role. No treatment has been established, but management of vascular risk factors and optimisation of glycaemic control could have therapeutic benefit. We identify possible opportunities for intervention to improve cognitive outcomes in people with type 2 diabetes, and suggest how treatment can be tailored to individual risk profiles and comorbidities.
    The lancet. Diabetes & endocrinology. 03/2014; 2(3):246-255.
  • Rachel A Whitmer
    The Lancet Diabetes & Endocrinology. 01/2014;
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    ABSTRACT: Background:Although those with type 2 diabetes have double the risk of dementia, potential racial/ethnic differences in dementia risk have not been explored in this population. We evaluated racial/ethnic differences in dementia and potential explanatory factors among older diabetes patients.Methods: We identified 22,171 diabetes patients without preexisting dementia, aged ≥60 years (14,546 non-Hispanic whites, 2,484 African Americans, 2,363 Latinos, 2,262 Asians, 516 Native Americans) from the Kaiser Permanente Northern California Diabetes Registry. We abstracted prevalent medical history (1/1/1996-12/31/1997) and dementia incidence (1/1/1998-12/31/2007) from medical records and calculated age-adjusted incidence densities. We fit Cox proportional hazards models adjusted for age, sex, education, diabetes duration, and markers of clinical control.Results:Dementia was diagnosed in 3,796 (17.1%) patients. Age-adjusted dementia incidence densities were highest among Native Americans (34/1,000 person-years) and African Americans (27/1,000 person-years) and lowest among Asians (19/1,000 person-years). In the fully-adjusted model, hazard ratios (95% CIs) (relative to Asians) were 1.64 (1.30-2.06) for Native Americans, 1.44 (1.24-1.67) for African Americans, 1.30 (1.15-1.47) for non-Hispanic whites, and 1.19 (1.02-1.40) for Latinos. Adjustment for diabetes-related complications and neighborhood deprivation index did not change results.Conclusions:Among type 2 diabetes patients followed for ten years, African Americans and Native Americans had a 40-60% greater risk of dementia compared to Asians, and risk was intermediate for non-Hispanic whites and Latinos. Adjustment for sociodemographics, diabetes-related complications, and markers of clinical control did not explain observed differences. Future studies should investigate why these differences exist and ways to reduce them.
    Diabetes care 11/2013; · 7.74 Impact Factor
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    ABSTRACT: Although patients with type 2 diabetes are twice as likely to develop dementia as those without this disease, prediction of who has the highest future risk is difficult. We therefore created and validated a practical summary risk score that can be used to provide an estimate of the 10 year dementia risk for individuals with type 2 diabetes. Using data from two longitudinal cohorts of patients with type 2 diabetes (aged ≥60 years) with 10 years of follow-up, we created (n=29 961) and validated (n=2413) the risk score. We built our prediction model by evaluating 45 candidate predictors using Cox proportional hazard models and developed a point system for the risk score based on the size of the predictor's β coefficient. Model prediction was tested by discrimination and calibration methods. Dementia risk per sum score was calculated with Kaplan-Meier estimates. Microvascular disease, diabetic foot, cerebrovascular disease, cardiovascular disease, acute metabolic events, depression, age, and education were most strongly predictive of dementia and constituted the risk score (C statistic 0·736 for creation cohort and 0·746 for validation cohort). The dementia risk was 5·3% (95% CI 4·2-6·3) for the lowest score (-1) and 73·3% (64·8-81·8) for the highest (12-19) sum scores. To the best of our knowledge, this is the first risk score for the prediction of 10 year dementia risk in patients with type 2 diabetes mellitus. The risk score can be used to increase vigilance for cognitive deterioration and for selection of high-risk patients for participation in clinical trials. Kaiser Permanente Community Benefit, National Institute of Health, Utrecht University, ZonMw, and Fulbright.
    The lancet. Diabetes & endocrinology. 11/2013; 1(3):183-90.
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    ABSTRACT: The objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors , aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population. Our second aim was to improve the CAIDE risk score by additional midlife risk factors. This retrospective cohort study was conducted in an integrated health care delivery system. A total of 9480 Kaiser Permanente members who participated in a health survey study (age range, 40-55 years) from 1964 to 1973 were included in this study. Dementia diagnoses from primary care and medical specialist visits were collected from January 1, 1994 to January 16, 2006, using International Classification of Diseases 9 codes 290.0, 290.1 for "possible dementia," and 331.0 and 290.4 for "specialist confirmed dementia." Risk model prediction and validation were examined with the C statistic, net reclassification improvement, and integrated discrimination improvement. Dementia risk per sum score was calculated with Kaplan-Meier estimates. A total of 2767 participants (25%) were diagnosed with any type of dementia, of which 1011 diagnoses (10.7%) were specialist-confirmed diagnoses. Average time between midlife examination and end of follow-up was 36.1 years. The CAIDE risk score replicated well with a C statistic of 0.75, quite similar to the original CAIDE C statistic of 0.78. The CAIDE score also predicted well within different race strata. Other midlife risk factors (central obesity, depressed mood, diabetes mellitus, head trauma, lung function, and smoking) did not improve predictability. The risk score allowed stratification of participants into those with 40-year low (9%) and high (29%) dementia risk. A combination of modifiable vascular risk factors in midlife is highly predictive of the likelihood of dementia decades later. Possible dementia prevention strategies should point to a life course perspective on maintaining vascular health.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 09/2013; · 14.48 Impact Factor
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    ABSTRACT: Background/Aims Telomere shortening is a biomarker of aging, but it is still unclear whether it directly influences aging-related health changes and mortality, or largely reflects the accumulating influences of environmental influences and declining health. Prior studies have reported associations between short telomeres and many health conditions. Mendelian syndromes and heritability studies demonstrate the biological underpinnings of telomere length (TL), yet other studies show that environmental and behavioral factors also influence telomere lengths. Methods As part of the RPGEH, the Genetic Epidemiology Research Study on Adult Health and Aging (GERA), a multi-ethnic cohort (average age = 63 years) has measured TL from saliva samples on over 100,000 individuals with linked electronic medical records. A survey of demographic and behavioral factors was conducted 2 years prior to saliva collection. With these data, we examined demographic relationships with TL, behavioral influences, and relationship of TL with all-cause mortality following sample collection. Results As expected, TL is inversely correlated with age, and women have longer telomeres than men except as young adults. All analyses controlled for age and gender. As seen in other studies, we find significantly longer TL among African Americans than other groups. TL is positively correlated with education and body mass index (BMI), and negatively correlated with cigarette smoking and alcohol consumption. We found no relationship with major depression or stress-related disorders, even when limited to recent episodes. We found that short TL was prospectively associated with mortality, although only those with the shortest TL were at increased risk; the association suggested a critical threshold of short TL determines effects on mortality. The association persisted even after adjustment of the demographic and behavioral factors such as age, sex, race, education, BMI, smoking, and alcohol consumption. Conclusions While this could indicate a direct effect of TL on health, it will also be important to examine the extent of pre-existing morbidities in these individuals to understand their possible role in the pathway between TL and longevity.
    Clinical Medicine &amp Research 09/2013; 11(3):146.
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    ABSTRACT: Background/Aims The Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment, and Health (RPGEH) provides a research resource to support investigations of environmental and genetic factors in the development of a wide variety of conditions. While the resource is still evolving with new data collection, it consists of data from surveys and electronic medical records on over 400,000 adult members of KPNC; biospecimens collected and stored on ~200,000 of these individuals; and data from genome-wide and telomere-length assays on ~110,000 of those who have contributed biospecimens; and linkage of these members to environmental, area-level databases. Methods The RPGEH was developed in part with the understanding that it would be made available to the scientific community for appropriate studies. An Access and Collaborations Core has developed procedures for submission of applications for research studies, their review, and decisions on approval and support. Review of proposals by an Applications Review Committee follows a two-step process, with a pre-application to assess feasibility (e.g., adequate numbers of the phenotype: availability of appropriate data, given inclusion criteria) and a full application to assess appropriateness of the study in the RPGEH context. Scientific merit; alignment with RPGEH guiding principles, including ethical, legal, and social implications; consistency with informed consents; potential overlap with prior approvals; and collaboration with a researcher affiliated with the Division of Research are among the criteria for approval. As an alternative for select analyses, genomic and selected phenotypic data will be available in the NIH database of genotypes and phenotypes (dbGaP) for the substantial subset of RPGEH participants who have consented to dbGaP deposition. Results As of October 31, 2012, the RPGEH has received 74 pre-applications and full applications for the use of its resources; only 6 pre-applications were not approved. In 2011-2012, 13 approved applications were funded by NIH and other agencies. Studies currently underway include genome-wide association studies of prostate cancer, bi-polar disorder, multiple sclerosis, and mammographic density. Conclusions Access to the unique and outstanding research resources of the RPGEH balances the mission of promoting research with the need to shepherd finite resources and safeguard member confidentiality.
    Clinical Medicine &amp Research 09/2013; 11(3):149.
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    ABSTRACT: Background/Aims Shortened telomeres have been associated with numerous adverse health outcomes. In addition, a number of environmental or external exposures, including smoking, air pollution and stress, have been reported to be associated with short telomeres. We sought to examine how neighborhood quality of participants in the RPGEH Genetic Epidemiology Research Study on Adult Health and Aging (GERA) cohort affected telomere length. Methods The GERA cohort is a multi-ethnic cohort (average age = 63 years) of over 100,000 individuals with linked electronic medical records and questionnaire data. Telomere length was determined from a saliva sample in the Blackburn Laboratory using the novel Automated Telomere Length Analysis System (ATLAS) to handle the required high throughput processing of samples. Each sample was assayed six times using qPCR. Relative telomere length (T/S) was obtained from the initial concentrations of the sample telomere (T) with the corresponding sample reference gene (S). The distribution of (T/S) was found to be positively skewed and a log transformation was used to normalize the distribution. The final telomere length end point was the difference in adjusted means of telomere length per standard deviation unit by accounting for age and gender. The NDI is a standardized composite score of neighborhood quality derived from eight 2000 US Census data variables related to poverty/income, occupation, family structure, education and unemployment and normalized to a 100-point scale at the block-group level. Results A higher NDI indicates greater neighborhood deprivation. The NDI was linked with residential address at time of sample collection. We observed a pattern of shorter telomere length with increasing level of neighborhood deprivation. The pattern persisted even after accounting for age, gender, race/ethnicity, smoking, BMI, and the presence of cardiovascular disease, diabetes and other comorbidity. Conclusions Our results suggest that neighborhood can adversely impact telomere length. Future plans will be discussed.
    Clinical Medicine &amp Research 09/2013; 11(3):147.
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    ABSTRACT: OBJECTIVES: Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with timing or type of HT use. METHODS: Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT. During this interval, 176 women developed incident AD. Cox proportional hazard models evaluated the association of HT use with AD, overall and in relation to timing, duration of use, and type (opposed vs unopposed) of HT. RESULTS: Women who used any type of HT within 5 years of menopause had 30% less risk of AD (95% confidence interval 0.49-0.99), especially if use was for 10 or more years. By contrast, AD risk was not reduced among those who had initiated HT 5 or more years after menopause. Instead, rates were increased among those who began "opposed" estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline (adjusted hazard ratio 1.93; 95% confidence interval 0.94-3.96). This last hazard ratio was similar to the ratio of 2.05 reported in randomized trial participants assigned to opposed HT. CONCLUSIONS: Association of HT use and risk of AD may depend on timing of use. Although possibly beneficial if taken during a critical window near menopause, HT (especially opposed compounds) initiated in later life may be associated with increased risk. The relation of AD risk to timing and type of HT deserves further study.
    Neurology 10/2012; · 8.25 Impact Factor
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    ABSTRACT: The risk of dementia is increased in people with type 2 diabetes mellitus (T2DM). This review gives an update on the relation between T2DM and specific dementia subtypes - i.e. Alzheimer's disease and vascular dementia - and underlying pathologies. We will show that while epidemiological studies link T2DM to Alzheimer's disease as well as vascular dementia, neuropathological studies attribute the increased dementia risk in T2DM patients primarily to vascular lesions in the brain. Risk factors for dementia among patients with T2DM are also addressed. Currently, there is evidence that microvascular complications, atherosclerosis and severe hypoglycemic events increase dementia risk. However, for a more complete understanding of risk factors for dementia in T2DM a life time perspective is needed. This should identify which individuals are at increased risk, what are vulnerable periods in life, and what are windows of opportunity for treatment. Currently, there are no DM specific treatments for dementia, but we will review observations from clinical trials that tried to prevent cognitive decline through intensified glycemic control and address other clinical implications of the association between T2DM and dementia.
    Experimental gerontology 08/2012; 47(11):858-64. · 3.34 Impact Factor
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    ABSTRACT: BACKGROUND: Reducing symptom burden is paramount at the end-of-life, but typically considered secondary to risk factor control in chronic disease, such as diabetes. Little is known about the symptom burden experienced by adults with type 2 diabetes and the need for symptom palliation. OBJECTIVE: To examine pain and non-pain symptoms of adults with type 2 diabetes over the disease course - at varying time points before death and by age. DESIGN: Survey follow-up study. PARTICIPANTS: 13,171 adults with type 2 diabetes, aged 30-75 years, from Kaiser Permanente, Northern California, who answered a baseline symptom survey in 2005-2006. MAIN MEASURES: Pain and non-pain symptoms were identified by self-report and medical record data. Survival status from baseline was categorized into ≤6, >6-24, or alive >24 months. KEY RESULTS: Mean age was 60 years; 48 % were women, and 43 % were non-white. Acute pain was prevalent (41.8 %) and 39.7 % reported chronic pain, 24.6 % fatigue, 23.7 % neuropathy, 23.5 % depression, 24.2 % insomnia, and 15.6 % physical/emotional disability. Symptom burden was prevalent in all survival status categories, but was more prevalent among those with shorter survival, p < .001. Adults ≥60 years who were alive >24 months reported more physical symptoms such as acute pain and dyspnea, whereas participants <60 years reported more psychosocial symptoms, such as depressed mood and insomnia. Adjustment for duration of diabetes and comorbidity reduced the association between age and pain, but did not otherwise change our results. CONCLUSIONS: In a diverse cohort of adults with type 2 diabetes, pain and non-pain symptoms were common among all patients, not only among those near the end of life. However, symptoms were more prevalent among patients with shorter survival. Older adults reported more physical symptoms, whereas younger adults reported more psychosocial symptoms. Diabetes care management should include not only good cardiometabolic control, but also symptom palliation across the disease course.
    Journal of General Internal Medicine 08/2012; · 3.28 Impact Factor
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    ABSTRACT: Central obesity is a risk factor for cognitive decline. Leptin is secreted by adipose tissue and has been associated with better cognitive function. Aging Mexican Americans have higher levels of obesity than non-Hispanic Whites, but no investigations examined the relationship between leptin and cognitive decline among them or the role of central obesity in this association. We analyzed 1,480 dementia-free older Mexican Americans who were followed over 10 years. Cognitive function was assessed every 12-15 months with the Modified Mini Mental State Exam (3MSE) and the Spanish and English Verbal Learning Test (SEVLT). For females with a small waist circumference (≤35 inches), an interquartile range difference in leptin was associated with 35% less 3MSE errors and 22% less decline in the SEVLT score over 10 years. For males with a small waist circumference (≤40 inches), an interquartile range difference in leptin was associated with 44% less 3MSE errors and 30% less decline in the SEVLT score over 10 years. There was no association between leptin and cognitive decline among females or males with a large waist circumference. Leptin interacts with central obesity in shaping cognitive decline. Our findings provide valuable information about the effects of metabolic risk factors on cognitive function.
    Dementia and Geriatric Cognitive Disorders 07/2012; 33(6):400-9. · 2.79 Impact Factor
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    ABSTRACT: Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia. To clarify the timing and nature of the association between depression and dementia. We examined depressive symptoms assessed in midlife (1964-1973) and late life (1994-2000) and the risks of dementia, Alzheimer disease (AD), and vascular dementia (VaD) (2003-2009) in a retrospective cohort study. Depressive symptoms were categorized as none, midlife only, late life only, or both. Cox proportional hazards models (age as timescale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD, or VaD. Kaiser Permanente Medical Care Program of Northern California. Thirteen thousand five hundred thirty-five long-term Kaiser Permanente members. Any medical record diagnosis of dementia or neurology clinic diagnosis of AD or VaD. Subjects had a mean (SD) age of 81.1 (4.5) years in 2003, 57.9% were women, and 24.2% were nonwhite. Depressive symptoms were present in 14.1% of subjects in midlife only, 9.2% in late life only, and 4.2% in both. During 6 years of follow-up, 22.5% were diagnosed with dementia (5.5% with AD and 2.3% with VaD). The adjusted hazard of dementia was increased by approximately 20% for midlife depressive symptoms only (hazard ratio, 1.19 [95% CI, 1.07-1.32]), 70% for late-life symptoms only (1.72 [1.54-1.92]), and 80% for both (1.77 [1.52-2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a 2-fold increase in AD risk (hazard ratio, 2.06 [95% CI, 1.67-2.55]), whereas subjects with midlife and late-life symptoms had more than a 3-fold increase in VaD risk (3.51 [2.44-5.05]). Depressive symptoms in midlife or in late life are associated with an increased risk of developing dementia. Depression that begins in late life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.
    Archives of general psychiatry 05/2012; 69(5):493-8. · 12.26 Impact Factor
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    ABSTRACT: Although depression is a risk factor for dementia in the general population, its association with dementia among patients with diabetes mellitus has not been well studied. To determine whether comorbid depression in patients with type 2 diabetes increases the risk of development of dementia. The Diabetes and Aging Study was a cohort investigation that surveyed a racially/ethnically stratified random sample of patients with type 2 diabetes. A large, integrated, nonprofit managed care setting in Northern California. A sample of 19,239 diabetes registry members 30 to 75 years of age. The Patient Health Questionnaire 8, International Classification of Diseases, Ninth Revision (ICD-9) diagnoses of depression, and/or antidepressant prescriptions in the 12 months prior to baseline were used to identify prevalent cases of depression. Clinically recognized dementia was identified among subjects with no prior ICD-9 Clinical Modification (ICD-9-CM) diagnoses of dementia. To exclude the possibility that depression was a prodrome of dementia, dementia diagnoses were only based on ICD-9-CM diagnoses identified in years 3 to 5 postbaseline. The risk of dementia for patients with depression and diabetes relative to patients with diabetes alone was estimated using Cox proportional hazard regression models that adjusted for sociodemographic, clinical, and health risk factors and health use. During the 3- to 5-year period, 80 of 3766 patients (2.1%) with comorbid depression and diabetes (incidence rate of 5.5 per 1000 person-years) vs 158 of 15,473 patients (1.0%) with diabetes alone (incidence rate of 2.6 per 1000 person-years) had 1 or more ICD-9-CM diagnoses of dementia. Patients with comorbid depression had a 100% increased risk of dementia during the 3 to 5 years postbaseline (adjusted hazard ratio, 2.02; 95% confidence interval, 1.73-2.35). Depression in patients with diabetes was associated with a substantively increased risk for development of dementia compared with those with diabetes alone.
    Archives of general psychiatry 12/2011; 69(4):410-7. · 12.26 Impact Factor
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    ABSTRACT: Four custom Axiom genotyping arrays were designed for a genome-wide association (GWA) study of 100,000 participants from the Kaiser Permanente Research Program on Genes, Environment and Health. The array optimized for individuals of European race/ethnicity was previously described. Here we detail the development of three additional microarrays optimized for individuals of East Asian, African American, and Latino race/ethnicity. For these arrays, we decreased redundancy of high-performing SNPs to increase SNP capacity. The East Asian array was designed using greedy pairwise SNP selection. However, removing SNPs from the target set based on imputation coverage is more efficient than pairwise tagging. Therefore, we developed a novel hybrid SNP selection method for the African American and Latino arrays utilizing rounds of greedy pairwise SNP selection, followed by removal from the target set of SNPs covered by imputation. The arrays provide excellent genome-wide coverage and are valuable additions for large-scale GWA studies.
    Genomics 08/2011; 98(6):422-30. · 3.01 Impact Factor
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    ABSTRACT: The success of genome-wide association studies has paralleled the development of efficient genotyping technologies. We describe the development of a next-generation microarray based on the new highly-efficient Affymetrix Axiom genotyping technology that we are using to genotype individuals of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH). The array contains 674,517 SNPs, and provides excellent genome-wide as well as gene-based and candidate-SNP coverage. Coverage was calculated using an approach based on imputation and cross validation. Preliminary results for the first 80,301 saliva-derived DNA samples from the RPGEH demonstrate very high quality genotypes, with sample success rates above 94% and over 98% of successful samples having SNP call rates exceeding 98%. At steady state, we have produced 462 million genotypes per week for each Axiom system. The new array provides a valuable addition to the repertoire of tools for large scale genome-wide association studies.
    Genomics 04/2011; 98(2):79-89. · 3.01 Impact Factor
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    ABSTRACT: Although previous research has shown that initiation of postmenopausal estrogen hormone therapy (HT) in late life increases risk of dementia, animal studies and some observational studies have suggested that midlife use of HT may be beneficial; however, this has not been rigorously investigated in large population-based studies. Our objective was to compare HT use in midlife with that in late life on risk of dementia among 5,504 postmenopausal female members of an integrated healthcare delivery system. HT use was determined at midlife (mean age, 48.7 years) from a survey in 1964 and in late life (mean age, 76 years) using pharmacy databases from 1994 to 1998. Risk of dementia diagnosis was evaluated with inpatient and outpatient diagnoses made in Neurology, Neuropsychology, and Internal Medicine from 1999 to 2008. Cox proportional hazard models were used to examine effects of HT use at different times on dementia risk with adjustment for age, education, race, body mass index, number of children, and comorbidities. A total of 1,524 women (27%) were diagnosed with dementia during the follow-up period. Compared to women never on HT, those taking HT only at midlife had a 26% decreased risk (multivariate adjusted hazards ratio [aHR], 0.74; 95% confidence interval [CI], 0.58-0.94 ), whereas those taking HT only in late life had a 48% increased risk (aHR, 1.48; 95% CI, 1.10-1.98), and women taking HT at both mid and late life had a similar risk of dementia (aHR, 1.02; 95% CI, 0.78-1.34 ). These findings suggest that use of HT in midlife only may protect against cognitive impairment, whereas HT initiation in late life could have deleterious effects.
    Annals of Neurology 01/2011; 69(1):163-9. · 11.19 Impact Factor

Publication Stats

2k Citations
287.59 Total Impact Points


  • 2005–2014
    • Kaiser Permanente
      Oakland, California, United States
  • 2013
    • University Medical Center Utrecht
      • Department of Neurology
      Utrecht, Utrecht, Netherlands
  • 2009–2013
    • University of California, San Francisco
      • • Department of Epidemiology and Biostatistics
      • • Department of Psychiatry
      San Francisco, California, United States
    • University of Kuopio
      • Department of Neurology
      Kuopio, Eastern Finland Province, Finland
  • 2011
    • University of Washington Seattle
      • Department of Psychiatry and Behavioral Sciences
      Seattle, WA, United States
  • 2010
    • University of Eastern Finland
      • Department of Neurology
      Kuopio, Province of Eastern Finland, Finland
    • Boston University
      • Department of Health Policy and Management
      Boston, MA, United States
  • 2006
    • University of Alabama at Birmingham
      • Division of Preventive Medicine
      Birmingham, AL, United States
  • 2003
    • University of California, Berkeley
      • School of Public Health
      Berkeley, CA, United States