Alzheimer's disease (AD) is a complex disorder influenced by environmental and genetic factors. Recent work has identified 11 AD markers in 10 loci. We used Genome-wide Complex Trait Analysis to ...analyze >2 million SNPs for 10,922 individuals from the Alzheimer's Disease Genetics Consortium to assess the phenotypic variance explained first by known late-onset AD loci, and then by all SNPs in the Alzheimer's Disease Genetics Consortium dataset. In all, 33% of total phenotypic variance is explained by all common SNPs. APOE alone explained 6% and other known markers 2%, meaning more than 25% of phenotypic variance remains unexplained by known markers, but is tagged by common SNPs included on genotyping arrays or imputed with HapMap genotypes. Novel AD markers that explain large amounts of phenotypic variance are likely to be rare and unidentifiable using genome-wide association studies. Based on our findings and the current direction of human genetics research, we suggest specific study designs for future studies to identify the remaining heritability of Alzheimer's disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective To determine whether higher cumulative use of benzodiazepines is associated with a higher risk of dementia or more rapid cognitive decline.Design Prospective population based ...cohort.Setting Integrated healthcare delivery system, Seattle, Washington.Participants 3434 participants aged ≥65 without dementia at study entry. There were two rounds of recruitment (1994-96 and 2000-03) followed by continuous enrollment beginning in 2004.Main outcomes measures The cognitive abilities screening instrument (CASI) was administered every two years to screen for dementia and was used to examine cognitive trajectory. Incident dementia and Alzheimer’s disease were determined with standard diagnostic criteria. Benzodiazepine exposure was defined from computerized pharmacy data and consisted of the total standardized daily doses (TSDDs) dispensed over a 10 year period (a rolling window that moved forward in time during follow-up). The most recent year was excluded because of possible use for prodromal symptoms. Multivariable Cox proportional hazard models were used to examine time varying use of benzodiazepine and dementia risk. Analyses of cognitive trajectory used linear regression models with generalized estimating equations.Results Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed Alzheimer’s disease. For dementia, the adjusted hazard ratios associated with cumulative benzodiazepine use compared with non-use were 1.25 (95% confidence interval 1.03 to 1.51) for 1-30 TSDDs; 1.31 (1.00 to 1.71) for 31-120 TSDDs; and 1.07 (0.82 to 1.39) for ≥121 TSDDs. Results were similar for Alzheimer’s disease. Higher benzodiazepine use was not associated with more rapid cognitive decline.Conclusion The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.
IMPORTANCE: Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a ...few studies suggest that anticholinergics may be associated with an increased risk for dementia. OBJECTIVE: To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia. DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses. EXPOSURES: Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time. MAIN OUTCOMES AND MEASURES: Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities. RESULTS: The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these 79.9% developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses. CONCLUSIONS AND RELEVANCE: Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.
Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis ...of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells) provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer's disease (LOAD). Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson's disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Type 2 diabetes confers a greater excess risk of cardiovascular disease in women than in men. Diabetes is also a risk factor for dementia, but whether the association is similar in women and men ...remains unknown. We performed a meta-analysis of unpublished data to estimate the sex-specific relationship between women and men with diabetes with incident dementia.
A systematic search identified studies published prior to November 2014 that had reported on the prospective association between diabetes and dementia. Study authors contributed unpublished sex-specific relative risks (RRs) and 95% CIs on the association between diabetes and all dementia and its subtypes. Sex-specific RRs and the women-to-men ratio of RRs (RRRs) were pooled using random-effects meta-analyses.
Study-level data from 14 studies, 2,310,330 individuals, and 102,174 dementia case patients were included. In multiple-adjusted analyses, diabetes was associated with a 60% increased risk of any dementia in both sexes (women: pooled RR 1.62 95% CI 1.45-1.80; men: pooled RR 1.58 95% CI 1.38-1.81). The diabetes-associated RRs for vascular dementia were 2.34 (95% CI 1.86-2.94) in women and 1.73 (95% CI 1.61-1.85) in men, and for nonvascular dementia, the RRs were 1.53 (95% CI 1.35-1.73) in women and 1.49 (95% CI 1.31-1.69) in men. Overall, women with diabetes had a 19% greater risk for the development of vascular dementia than men (multiple-adjusted RRR 1.19 95% CI 1.08-1.30; P < 0.001).
Individuals with type 2 diabetes are at ∼60% greater risk for the development of dementia compared with those without diabetes. For vascular dementia, but not for nonvascular dementia, the additional risk is greater in women.
Delirium is common, leads to other adverse outcomes, and is costly. However, it often remains unrecognized in most clinical settings. The Confusion Assessment Method (CAM) is the most widely used ...diagnostic algorithm, and operationalizing its features would be a substantial advance for clinical care.
To derive the 3D-CAM, a new 3-minute diagnostic assessment for CAM-defined delirium, and validate it against a clinical reference standard.
Derivation and validation study.
4 general medicine units in an academic medical center.
201 inpatients aged 75 years or older.
20 items that best operationalized the 4 CAM diagnostic features were identified to create the 3D-CAM. For prospective validation, 3D-CAM assessments were administered by trained research assistants. Clinicians independently did an extensive assessment, including patient and family interviews and medical record reviews. These data were considered by an expert panel to determine the presence or absence of delirium and dementia (reference standard). The 3D-CAM delirium diagnosis was compared with the reference standard in all patients and subgroups with and without dementia.
The 201 participants in the prospective validation study had a mean age of 84 years, and 28% had dementia. The expert panel identified 21% with delirium, 88% of whom had hypoactive or normal psychomotor features. Median administration time for the 3D-CAM was 3 minutes (interquartile range, 2 to 5 minutes), sensitivity was 95% (95% CI, 84% to 99%), and specificity was 94% (CI, 90% to 97%). The 3D-CAM did well in patients with dementia (sensitivity, 96% CI, 82% to 100%; specificity, 86% CI, 67% to 96%) and without dementia (sensitivity, 93% CI, 66% to 100%; specificity, 96% CI, 91% to 99%).
Limited to single-center, cross-sectional, and medical patients only.
The 3D-CAM operationalizes the CAM algorithm using a 3-minute structured assessment with high sensitivity and specificity relative to a reference standard and could be an important tool for improving recognition of delirium.
National Institute on Aging.
Despite the success of large-scale genome-wide association studies (GWASs) on complex traits, our understanding of their genetic architecture is far from complete. Jointly modeling multiple traits’ ...genetic profiles has provided insights into the shared genetic basis of many complex traits. However, large-scale inference sets a high bar for both statistical power and biological interpretability. Here we introduce a principled framework to estimate annotation-stratified genetic covariance between traits using GWAS summary statistics. Through theoretical and numerical analyses, we demonstrate that our method provides accurate covariance estimates, thereby enabling researchers to dissect both the shared and distinct genetic architecture across traits to better understand their etiologies. Among 50 complex traits with publicly accessible GWAS summary statistics (Ntotal≈ 4.5 million), we identified more than 170 pairs with statistically significant genetic covariance. In particular, we found strong genetic covariance between late-onset Alzheimer disease (LOAD) and amyotrophic lateral sclerosis (ALS), two major neurodegenerative diseases, in single-nucleotide polymorphisms (SNPs) with high minor allele frequencies and in SNPs located in the predicted functional genome. Joint analysis of LOAD, ALS, and other traits highlights LOAD’s correlation with cognitive traits and hints at an autoimmune component for ALS.
Objective
To estimate dementia's incremental cost to the traditional Medicare program.
Data Sources
Health and Retirement Study (HRS) survey‐linked Medicare part A and B claims from 1991 to 2012.
...Study Design
We compared Medicare expenditures for 60 months following a claims‐based dementia diagnosis to those for a randomly selected, matched comparison group.
Data Collection/Extraction Methods
We used a cost estimator that accounts for differential survival between individuals with and without dementia and decomposes incremental costs into survival and cost intensity components.
Principal Findings
Dementia's five‐year incremental cost to the traditional Medicare program is approximately $15 700 per patient, nearly half of which is incurred in the first year after diagnosis. Shorter survival with dementia mitigates the incremental cost by about $2650. Increased costs for individuals with dementia were driven by more intensive use of Medicare part A covered services. The incremental cost of dementia was about $7850 higher for females than for males because of sex‐specific differential mortality associated with dementia.
Conclusions
Dementia's cost to the traditional Medicare program is significant. Interventions that target early identification of dementia and preventable inpatient and post‐acute care services could produce substantial savings.
IMPORTANCE: Visual function is important for older adults. Interventions to preserve vision, such as cataract extraction, may modify dementia risk. OBJECTIVE: To determine whether cataract extraction ...is associated with reduced risk of dementia among older adults. DESIGN, SETTING, AND PARTICIPANTS: This prospective, longitudinal cohort study analyzed data from the Adult Changes in Thought study, an ongoing, population-based cohort of randomly selected, cognitively normal members of Kaiser Permanente Washington. Study participants were 65 years of age or older and dementia free at enrollment and were followed up biennially until incident dementia (all-cause, Alzheimer disease, or Alzheimer disease and related dementia). Only participants who had a diagnosis of cataract or glaucoma before enrollment or during follow-up were included in the analyses (ie, a total of 3038 participants). Data used in the analyses were collected from 1994 through September 30, 2018, and all data were analyzed from April 6, 2019, to September 15, 2021. EXPOSURES: The primary exposure of interest was cataract extraction. Data on diagnosis of cataract or glaucoma and exposure to surgery were extracted from electronic medical records. Extensive lists of dementia-related risk factors and health-related variables were obtained from study visit data and electronic medical records. MAIN OUTCOMES AND MEASURES: The primary outcome was dementia as defined by Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Multivariate Cox proportional hazards regression analyses were conducted with the primary outcome. To address potential healthy patient bias, weighted marginal structural models incorporating the probability of surgery were used and the association of dementia with glaucoma surgery, which does not restore vision, was evaluated. RESULTS: In total, 3038 participants were included (mean SD age at first cataract diagnosis, 74.4 (6.2) years; 1800 women (59%) and 1238 men (41%); and 2752 (91%) self-reported White race). Based on 23 554 person-years of follow-up, cataract extraction was associated with significantly reduced risk (hazard ratio, 0.71; 95% CI, 0.62-0.83; P < .001) of dementia compared with participants without surgery after controlling for years of education, self-reported White race, and smoking history and stratifying by apolipoprotein E genotype, sex, and age group at cataract diagnosis. Similar results were obtained in marginal structural models after adjusting for an extensive list of potential confounders. Glaucoma surgery did not have a significant association with dementia risk (hazard ratio, 1.08; 95% CI, 0.75-1.56; P = .68). Similar results were found with the development of Alzheimer disease dementia. CONCLUSIONS AND RELEVANCE: This cohort study found that cataract extraction was significantly associated with lower risk of dementia development. If validated in future studies, cataract surgery may have clinical relevance in older adults at risk of developing dementia.
BACKGROUND:Patient-reported outcomes (PROs) are gaining recognition as key measures for improving the quality of patient care in clinical care settings. Three factors have made the implementation of ...PROs in clinical care more feasibleincreased use of modern measurement methods in PRO design and validation, rapid progression of technology (eg, touchscreen tablets, Internet accessibility, and electronic health records), and greater demand for measurement and monitoring of PROs by regulators, payers, accreditors, and professional organizations. As electronic PRO collection and reporting capabilities have improved, the challenges of collecting PRO data have changed.
OBJECTIVES:To update information on PRO adoption considerations in clinical care, highlighting electronic and technical advances with respect to measure selection, clinical workflow, data infrastructure, and outcomes reporting.
METHODS:Five practical case studies across diverse health care settings and patient populations are used to explore how implementation barriers were addressed to promote the successful integration of PRO collection into the clinical workflow. The case studies address selecting and reporting of relevant content, workflow integration, previsit screening, effective evaluation, and electronic health record integration.
CONCLUSIONS:These case studies exemplify elements of well-designed electronic systems, including response automation, tailoring of item selection and reporting algorithms, flexibility of collection location, and integration with patient health care data elements. They also highlight emerging logistical barriers in this area, such as the need for specialized technological and methodological expertise, and design limitations of current electronic data capture systems.
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