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Biomedical subjects

Eric B Larson

Publications and source records attributed to Eric B Larson.

At least 19 recordsLinked to original sources
PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-&#x3b2; 42 (A&#x3b2;42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF A&#x3b2;42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In A&#x3b2;42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p&#x2009;=&#x2009;0.04) and rs13115400 near LINC00290 (p&#x2009;=&#x2009;0.002). These loci showed stronger associations among females (&#x3b2;&#x2009;=&#x2009;-&#x2009;0.03, p&#x2009;=&#x2009;4.25&#x2009;&#xd7;&#x2009;10-8; &#x3b2;&#x2009;=&#x2009;0.03, p&#x2009;=&#x2009;3.97&#x2009;&#xd7;&#x2009;10-8) than males (&#x3b2;&#x2009;=&#x2009;-&#xa0;0.02, p&#x2009;=&#x2009;0.009; &#x3b2;&#x2009;=&#x2009;0.01, p&#x2009;=&#x2009;0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values&#x2009;<&#x2009;0.02) but not males (p&#x2009;>&#x2009;0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p&#x2009;=&#x2009;0.004), driven by a stronger association among females (&#x3b2;&#x2009;=&#x2009;0.05, p&#x2009;=&#x2009;4.57&#x2009;&#xd7;&#x2009;10-10) compared to males (&#x3b2;&#x2009;=&#x2009;0.02, p&#x2009;=&#x2009;0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale&#x2009;=&#x2009;0.047; pmale&#x2009;=&#x2009;0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p&#x2009;=&#x2009;0.006; CLDN16 p&#x2009;=&#x2009;0.002) but not males (p&#x2009;&#x2265;&#x2009;0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 &#xd7; 10(-9), joint analysis P (P(J)) = 1.7 &#xd7; 10(-9); stages 1, 2 and 3, P(M) = 8.2 &#xd7; 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 &#xd7; 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 &#xd7; 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 &#xd7; 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 &#xd7; 10(-10), P(J) = 5.2 &#xd7; 10(-11)), CLU (rs1532278; P(M) = 8.3 &#xd7; 10(-8), P(J) = 1.9 &#xd7; 10(-8)), BIN1 (rs7561528; P(M) = 4.0 &#xd7; 10(-14), P(J) = 5.2 &#xd7; 10(-14)) and PICALM (rs561655; P(M) = 7.0 &#xd7; 10(-11), P(J) = 1.0 &#xd7; 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Primary care: the next renaissance.

Three decades ago, a renaissance helped create the foundations of primary care as we know it today. In recent years, however, new challenges have confronted primary care. We believe that the current challenges can be overcome and may, in fact, present an opportunity for a new renaissance of primary care to address the needs of our population. In this paper, we suggest seven core principles and a set of actions that will support a renaissance in, and a positive future for, primary care. The seven principles are 1) Health care must be organized to serve the needs of patients; 2) the goal of primary care systems should be the delivery of the highest-quality care as documented by measurable outcomes; 3) information and information systems are the backbone of the primary care process; 4) current health care systems must be reconstructed; 5) the health care financing system must support excellent primary care practice; 6) primary care education must be revitalized, with an emphasis on new delivery models and training in sites that deliver excellent primary care; and 7) the value of primary care practice must be continually improved, documented, and communicated. At the start of the 21st century, a vital, patient-centered primary care system has much to offer a rapidly changing population with increasingly diverse needs and expectations. If we keep the needs of persons and patients clearly in sight and design systems to meet those needs, primary care will thrive and our patients will be well served.

Delivery of Health Care↗
PubMed2003

Alcohol, aging, and cognitive performance: a cross-cultural comparison.

This study investigated the relationship between alcohol consumption and cognitive performance in two culturally diverse community-based populations. METHODS. A cross-sectional analysis was used including Japanese Americans (n = 1,836) and Caucasians (n = 2,581) aged 65 and older. Cognitive performance was measured using the Cognitive Abilities Screening Instrument (CASI) (0 to 100 point scale) and reaction time. RESULTS. Multivariate analysis revealed significant cultural and gender differences with cognitive performance. Compared to abstainers, Caucasian drinkers scored higher than Japanese American drinkers on the CASI (adjusted means = 93.4 versus 91.6). In contrast, Japanese American drinkers scored faster than Caucasian drinkers on choice reaction time (adjusted means = 505 versus 579 milliseconds). DISCUSSION. Results showed that current drinking was associated with better cognition in both the Caucasian and Japanese American groups. Longitudinal studies are needed to support the possible protective effects of alcohol on cognition and explore whether culture may modify this apparent benefit.

Age Factors↗
PubMed2003

Birth outcomes among American Indian/Alaska Native women with diabetes in pregnancy.

OBJECTIVE: To describe perinatal outcomes and maternal characteristics among American Indian/Alaska Native (AI/AN) women with diabetes in pregnancy. STUDY DESIGN: A retrospective analysis of live births to AI/AN, African American and white women with diabetes (242,715) during pregnancy for the 1989-1991 period (latest available at the time of study) was conducted utilizing a linked birth/infant death database from the National Center for Health Statistics. AI/AN perinatal outcomes and maternal characteristics were compared to those of African American and white women. Similar analyses compared urban and rural AI/AN populations. RESULTS: AI/AN women were more likely than white women to receive inadequate prenatal care (10.4%), to have higher rates of pregnancy-induced hypertension (9.1%) and to have significantly lower rates of primary cesarean delivery (16.9% vs. 22.3%). The rate of macrosomia among births to AI/AN women (24.2%) was notably higher as compared to that in the white population (17.9%). Rates of musculoskeletal and chromosomal anomalies were also higher among AI/AN women, 9 and 4, respectively, per 1,000 live births, as compared to 6 and 2 per 1,000 for the white population. CONCLUSION: Multiple maternal risk factors and birth outcomes demonstrate the need for further research to evaluate methods of improving care in this population.

Black or African American↗
PubMed2002

Dementia and Alzheimer disease incidence: a prospective cohort study.

CONTEXT: Age-specific incidence rates for dementia and Alzheimer disease (AD) are important for research and clinical practice. Incidence estimates for the United States are few and vary with the population sampled and study design; we present data that will contribute to a consensus of these rates. OBJECTIVES: To provide age-specific incidence estimates for dementia and AD and to estimate the association of sex, educational level, and apolipoprotein E genotype with onset. DESIGN: Prospective cohort study; begun in 1994 with follow-up interviews every 2 years. SETTING: Members of community-based, large health maintenance organization with demographics consistent with the surrounding base population; diagnostic evaluation by university-based study clinicians. SUBJECTS: Random sample of subjects aged 65 years or older from the base population; dementia free, nonnursing home residents. Of 5422 who were eligible, 2581 were enrolled, and 2356 had at least 1 follow-up evaluation (10 591 person-years of observation). MAIN OUTCOME MEASURE: Dementia and Alzheimer disease diagnoses were based on standard criteria. Age-specific incidence rates were calculated using a person-years approach with Poisson distribution confidence intervals. Cox proportional hazards model analysis was used to examine other factors. RESULTS: Two hundred fifteen cases of dementia and 151 cases of AD were diagnosed. Incidence rates for dementia and AD increase across the 5-year age groups; AD rates rise from 2.8 per 1000 person-years (age group, 65-69 years) to 56.1 per 1000 person-years in the older than 90-year age group. The rates nearly triple from the 75-to-79-year and 80-to-84-year age groups, but the relative increase is much less thereafter. Sex was not associated with AD onset. Educational level (>15 years vs <12 years) was associated with a decreased risk of AD; however, the association was also dependent on the baseline cognitive screening test score. CONCLUSIONS: Our dementia and AD incidence rates are consistent with recent US and European cohort studies, providing clinicians and researchers new information concerning the reproducibility of incidence estimates across settings. Increased risk was associated with age and the apolipoprotein E genotype; also with a low baseline cognitive screening test score. Educational level was inversely associated with the risk of dementia and positively associated with the baseline cognitive test score; thus, detection of AD by the screening test could also be influenced by educational level.

Age Factors↗
PubMed2002

Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study.

BACKGROUND: Hippocampal sclerosis (HS) is a neuropathologic finding characterized by neuronal loss and gliosis in the CA-1 and subiculum of the hippocampus. Previous studies of HS have shown that this is a common postmortem finding in elderly subjects with dementia. However, these studies were from selected samples and therefore are not necessarily representative of patients seen in the general medical community. OBJECTIVES: To examine the clinical and pathologic characteristics of HS in a community-based case series of dementia and to compare these characteristics with those observed in subjects with Alzheimer disease (AD) from the same study sample. METHODS: One hundred thirty-four autopsy cases were available from a community-based registry of dementia. Sixteen cases (12%) had a postmortem diagnosis of HS. Thirty-two comparison control cases with a neuropathologic diagnosis of AD were selected from the same files. Each case of HS was reviewed for HS neuropathologic features, including severity, distribution, and additional pathologic processes. Blinded review of clinical characteristics for the HS and control groups was performed to assess risk factors. RESULTS: There was a wide range of severity and distribution of HS lesions between cases and substantial variability in lesion severity and age within individual cases. Serial neuropsychologic and behavioral assessments revealed similar clinical features and rates of dementia progression between HS and AD groups. Of all neuropsychologic tests performed at enrollment, only enhanced performance on Trails A differentiated the HS from the AD group (64 seconds, 0 errors vs 114 seconds, 0.6 errors; P< or = .05). The number of AD cases with at least 1 apolipoprotein epsilon 4 allele was significantly greater than the HS cases (61% vs 31%; chi(2) = 3.81, P< or = .05). Although medical record review indicated higher frequencies of clinical stroke and neuroradiologic white matter abnormalities in the HS group, risk factors for vascular disease and neuropathologic evidence of cerebrovascular disease did not differ between the groups. CONCLUSIONS: Our results suggest that HS is a frequent pathologic finding in community-based dementia. Individuals with HS have similar initial symptoms and rates of dementia progression to those with AD and therefore are frequently misclassified as having AD. Our clinical and pathologic findings suggest that HS has characteristics of a progressive disorder although the underlying cause remains elusive.

Age of Onset↗
PubMed2002

Callosal function in multiple sclerosis: bimanual motor coordination.

Evidence of callosal dysfunction in patients with multiple sclerosis (MS) was examined using a test of bimanual coordination. MS patients were slower than non-patients on the Bimanual Coordination Test (BCT) on both unimanual trials (simple motor speed) and bimanual trials (intermanual coordination). Further, when compared to normals, MS patients exhibited a substantially greater difference between bimanual and unimanual response time, suggesting a deficit in interhemispheric motor interactions. A subgroup of MS subjects who showed markedly inefficient callosal transmission had previously been identified on the basis of abnormal evoked potentials (low amplitude cross-callosal evoked potentials). In comparisons of MS subgroups, the deficit in bimanual motor coordination was found only in MS patients with EP evidence of inefficient callosal transmission. These data support the conclusion that deficits in bimanual motor coordination occur in MS and that these deficits are related to callosal dysfunction.

Adult↗
PubMed2002

Older adults and functional decline: a cross-cultural comparison.

BACKGROUND: The study was conducted to examine the relationships between functional decline, health risk factors, lifestyle practices, and demographic variables in two culturally diverse, community-based samples of White and Japanese American older adults. DESIGN: The study was an analysis of data from two ongoing studies of aging and dementia in King County, Washington. Functional status at baseline was evaluated, and factors associated with functional decline over a 4-year follow-up period were identified. The sample included 1,083 Japanese American and 1,011 White cognitively intact, community-dwelling adults aged 65 and older, who had no functional limitations at baseline and participated in at least one follow-up examination. RESULTS: In 4 years of follow-up, 70% of the subjects reported no increase in functional limitation, and fewer than 5% of subjects declined in five or more activities. Risk factors associated with functional decline included increased age, female gender, medical comorbidity (particularly cerebrovascular disease, arthritis, and hypertension), elevated body mass index, poorer self-perceived health, and smoking. Depression and diabetes were also significant for persons with the greatest functional decline over the 4-year follow-up. Japanese speakers were significantly less likely to decline over the follow-up period than White or English-speaking Japanese American subjects. However, Japanese speakers were more likely to discontinue participation during the follow-up period, and may also have been more likely to underreport symptoms of functional decline. CONCLUSIONS: The present study provides further support that healthy lifestyle practices and prevention of chronic disease are important for maintaining functional independence in older adults. Japanese-speaking subjects were less likely to decline over time, although this could be due in part to differential dropout and reporting bias. These findings have important implications for the design and interpretation of longitudinal studies of older adults. Researchers interested in the effects of ethnicity on health and aging should be cognizant of differences in recruitment and enrollment strategies among studies, and the ways in which these affect study findings. This study also demonstrates the importance of devoting adequate resources to minimize dropouts, and of including measures of health and functioning that are culturally equivalent and less reliant on self-report data.

Aged↗
PubMed2002

Similarities and differences in attitudes toward long-term care between Japanese Americans and Caucasian Americans.

The purpose of this study was to compare attitudes toward the use of long-term care between older Japanese Americans (n = 1,244) and older Caucasian Americans (n = 1,354). When presented with a hypothetical situation in which they have dementia, 39% of older Japanese Americans and 42% of older Caucasians intended to be cared for at home, whereas 53% versus 38%, respectively, intended to use nursing home care (P <.001). If the hypothetical situation was hip fracture, 81% of older Japanese Americans and 72% of older Caucasians intended to be cared for at home, with 13% of both groups intending to use nursing home care (P = NS). The subjects' perceptions of what their families, friends, ministers, and communities would want them to choose differed, with more uncertainty among Caucasians (P <.001). For provision of home care, Japanese Americans were more likely to rely on loved ones than Caucasians, who were more likely to rely on paid providers. Multivariate logistic regression showed ethnicity to be independently related to intention to use nursing home care in the dementia scenario, controlling for demographic variables. Being married lowered the odds of intending to use nursing homes in any situation. We conclude that Caucasian Americans intend to use paid home health care at higher rates than Japanese Americans if they become disabled by dementia. Japanese Americans demonstrated more certainty about the influences of others on their opinions, suggesting a more stable cultural norm in this population, and intended to use more nursing home care in the event of permanent debility (dementia).

Aged↗
PubMed2002

Predictors of functional change: a longitudinal study of nondemented people aged 65 and older.

OBJECTIVES: To identify factors associated with functional change in an older population and investigate interactions among selected potential risk factors. DESIGN: A population-based prospective cohort study. SETTING: A random sample was selected from the Group Health Cooperative members in the Seattle area from 1994 to 1996 and followed biennially. PARTICIPANTS: Two thousand five hundred eighty-one people aged 65 and older, cognitively intact at baseline. MEASUREMENTS: Functional status was measured by activities of daily living, instrumental activities of daily living, and performance-based physical function testing. RESULTS: The cohort status at the time of these analyses was: deceased, 391; withdrawn, 179; dementia, 152; and on study, 1,873. The mean follow-up time was 3.4 years. Using linear regressions with Generalized Estimating Equation, selected medical conditions (diabetes mellitus, hypertension, coronary heart disease, cerebrovascular disease (CVD), osteoporosis, arthritis, and cancer), low cognitive function, depression, and smoking were associated with worse functional outcomes. Exercise and moderate alcohol use were associated with better functional outcomes. Over the follow-up period, coronary heart disease, CVD, and depression were associated with increased rates of functional decline. Exercise and moderate alcohol consumption were associated with decreased rates of functional decline. Significant interactions were observed between exercise and coronary heart disease, moderate alcohol use and CVD, and cognition and CVD. CONCLUSIONS: Our study has identified not only risk factors associated with functional decline but also the interactions among these factors. These observations, along with other published research, add to the growing understanding of the underlying process of functional change and could provide a basis to design effective strategies to delay functional decline.

Activities of Daily Living↗
PubMed2002

Measuring, monitoring, and reducing medical harm from a systems perspective: a medical director's personal reflections.

The author describes five critical elements for reducing and, ultimately, preventing harm to patients-from a systems perspective. In the element called leadership and culture, leaders must advocate patient safety as a primary goal and foster an institutional culture where change that promote patient safety can occur. In internal surveillance, systems are established to actively monitor for deviations in quality and guide efforts to engineer risk of harm out of the institution's practices; they can also demonstrate absence of risk or harm. Although incident reporting can be controversial and is sometimes avoided because its use in "blame attacks," etc., it can be valuable if built on a continuous improvement approach and a system approach to error prevention. External surveillance involves the identification and response to "sentinel events," such as wrong-sided surgery, and serves to remind all those involved in care just how risky and unforgiving medical practice can be. Finally, those involved in promoting safety must believe that hazard and risk are not inevitable and can be managed. The author illustrates this approach by describing his hospital's successful efforts to prevent the rise of aspergillus infections during a major hospital construction project. The author closes by describing selected challenges and opportunities to reduce harm from a systems perspective, such as using teams, involving patients and the public, using lessons learned from other industries with strong safety cultures, and using advances in information systems for a variety of safety-oriented tasks.

Culture↗
PubMed2002

Research agenda for understanding Alzheimer disease in diverse populations: work group on cultural diversity, Alzheimer's association.

The emerging evidence of ethnic variations in apolipoprotein polymorphism and Alzheimer disease risk shows that one cannot generalize findings based on a single cultural group too broadly ( Tang et al., 2001). Presence of one apolipoprotein E epsilon 4 allele is a stronger risk factor for Alzheimer disease in whites and Asians than in blacks ( Farrer et al., 1997). Environmental or genetic cofactors may modulate the effects of epsilon 4 on beta-amyloid metabolism differently in different subpopulations ( Shadlen, 1998). Recognizing this, the Alzheimer's Association has extended its goals to strengthen the scientific information base on the interactions of population diversity and Alzheimer disease heterogeneity ( NIA, 1998). This new focus is timely since minority elderly are the most rapidly increasing segment of the elderly population ( Lilienfeld and Perl, 1994, Brookmeyer et al., 1998). In this article, the authors highlight recent progress in research on Alzheimer disease among culturally diverse populations with a special emphasis on gaps in the knowledge base. The authors recommend four priorities for future Alzheimer disease research: (1) determine whether genetic causative factors interact differently in different populations; (2) reexamine the nature and role of cerebral ischemia and infarction and variations in symptom severity of Alzheimer disease; (3) explore the interaction of genes and environmental influences that are protective against Alzheimer disease; and (4) recruit and enroll ethnically diverse subjects in Alzheimer disease clinical trials.

Aged↗
PubMedDate not supplied

Mitochondrial genetic variants and Alzheimer disease: a case-control study of the T4336C and G5460A variants.

The T4336C mitochondrial genetic variant was associated with Alzheimer disease in several previous studies. Recent investigations, however, failed to confirm this association. We tested this association in newly diagnosed Alzheimer disease cases and controls of similar age and gender recruited from an established HMO serving Seattle, Washington and surrounding areas. In this, the largest case-control study reported to date, the T4336C variant was not associated with Alzheimer disease overall (present in 6 of 236 cases and 7 of 328 controls; odds ratio = 1.20, 95% CI 0.33 to 4.22). There was evidence of effect modification by Apolipoprotein E (APOE) status--among subjects with an APOE epsilon 4 allele, the T4336C variant was associated with disease (present in 5 of 139 cases and none of 82 controls; odds ratio = infinity, 95% CI 0.73 to infinity). APOE may be an important modifier of the T4336C effect, potentially explaining variable findings across previous studies. Alternatively, the positive findings reported to date may simply reflect the problem of "type I" error inherent in genetic association studies. Substantially larger samples than are currently available would be required to resolve this question. G5460(A/T) variants were also investigated and found not to be associated with Alzheimer disease.

Aged↗