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2.
Sci Rep ; 9(1): 14498, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601890

RESUMO

Adult neurogenesis occurs in the dentate gyrus of the hippocampus during adulthood and contributes to sustaining the hippocampal formation. To investigate whether neurogenesis-related pathways are associated with hippocampal volume, we performed gene-set enrichment analysis using summary statistics from a large-scale genome-wide association study (N = 13,163) of hippocampal volume from the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium and two year hippocampal volume changes from baseline in cognitively normal individuals from Alzheimer's Disease Neuroimaging Initiative Cohort (ADNI). Gene-set enrichment analysis of hippocampal volume identified 44 significantly enriched biological pathways (FDR corrected p-value < 0.05), of which 38 pathways were related to neurogenesis-related processes including neurogenesis, generation of new neurons, neuronal development, and neuronal migration and differentiation. For genes highly represented in the significantly enriched neurogenesis-related pathways, gene-based association analysis identified TESC, ACVR1, MSRB3, and DPP4 as significantly associated with hippocampal volume. Furthermore, co-expression network-based functional analysis of gene expression data in the hippocampal subfields, CA1 and CA3, from 32 normal controls showed that distinct co-expression modules were mostly enriched in neurogenesis related pathways. Our results suggest that neurogenesis-related pathways may be enriched for hippocampal volume and that hippocampal volume may serve as a potential phenotype for the investigation of human adult neurogenesis.

3.
World J Surg ; 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605180

RESUMO

BACKGROUND: The extent to which obesity and genetics determine postoperative complications is incompletely understood. METHODS: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. RESULTS: Individuals with overweight or obese BMI (≥25 kg/m2) had increased risk of incisional hernia (odds ratio [OR] 1.7-5.5, p < 3.1 × 10-20), and people with obesity (BMI ≥ 30 kg/m2) had increased risk of postoperative infection (OR 1.2-2.3, p < 2.5 × 10-5). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8-2.5], p = 1.4 × 10-6) and postoperative infection (OR 1.6 [95% CI 1.4-1.9], p = 3.1 × 10-6). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures. CONCLUSIONS: Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.

4.
Brain ; 142(9): 2581-2589, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31497858

RESUMO

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

5.
Am J Manag Care ; 25(8): e247-e253, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419102

RESUMO

OBJECTIVES: We conducted a systematic review of studies reporting the direct healthcare costs of treating older adults with diagnosed Alzheimer disease and related dementias (ADRD) within private Medicare managed care plans. STUDY DESIGN: A systematic review of all studies published in English reporting original empirical analyses of direct costs for older adults with ADRD in Medicare managed care. METHODS: All papers indexed in PubMed or Web of Science reporting ADRD costs within Medicare managed care plans from 1983 through 2018 were identified and reviewed. RESULTS: Despite the growth in Medicare managed care enrollment, only 9 papers report the costs of care for individuals with ADRD within these plans, and only 1 study reports data less than 10 years old. This limited literature reports wide ranges for ADRD-attributable costs, with estimates varying from $3738 to $8726 in annual prevalent costs and $8938 to $38,794 in 1-year immediate postdiagnosis incident costs. Reviewed studies also used varied study populations, case and cost ascertainment methods, and analytic methods, making cross-study comparisons difficult. CONCLUSIONS: The expected continued growth in Medicare managed care enrollment, coupled with the large and growing impact of ADRD on America's healthcare delivery and finance systems, requires more research on the cost of ADRD within managed care. This research should use more consistent approaches to identify ADRD prevalence and provide more detail regarding which components of care are included in analyses and how the costs of care are captured and measured.

6.
J Alzheimers Dis ; 70(2): 611-619, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256124

RESUMO

BACKGROUND: There is considerable heterogeneity in clinical presentation among people with late-onset Alzheimer's disease (LOAD). We have categorized people with LOAD into subgroups based on relative impairments across cognitive domains. These 6 groups are people with no relatively impaired domains (AD-No Domains), 4 groups with one relatively impaired domain (AD-Memory, AD-Executive, AD-Language, and AD-Visuospatial), and a group with multiple relatively impaired domains (AD-Multiple Domains). Our previous analysis demonstrated that genetic factors vary across cognitively-defined LOAD groups. OBJECTIVE: To determine whether risks associated with depression and traumatic brain injury with loss of consciousness (TBI) for cognitively defined LOAD subgroups are similar. METHODS: We used cognitive data at LOAD diagnosis from three prospective cohort studies to determine cognitively-defined subgroups. We compared subgroups in endorsement of items from the Centers for Epidemiological Studies Depression (CES-D) scale and history of TBI. RESULTS: Among 1,505 people with LOAD from the three studies, there were substantial differences across subgroups in total CES-D score, with lower scores (less depression) for people with AD with relative impairments in memory (AD-Memory) compared to those in other groups. Differences were noteworthy for the sleep-related item of the CES-D, as people with AD-Memory were less likely to report restless sleep than people in other groups. There were no differences in TBI history across groups. CONCLUSIONS: Differences in risk factor associations across subgroups such as differences in endorsement of depression symptoms and restless sleep provide support for the hypothesis that there are biologically coherent subgroups of AD.

7.
AIDS Care ; : 1-9, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189333

RESUMO

Low perceived social support (SS) negatively impacts health outcomes. We developed a measure of perceived SS for use in HIV care. We sought and categorized legacy items, selecting strongest items within categories. We elicited SS concepts from patients in English/Spanish, coded transcripts to match item pool content, and developed new items for salient unrepresented content. In focus groups, patients prioritized highly-matched items. We conducted cognitive interviews on high-priority items, and validity testing on final items against two legacy measures. From interviews (n = 32), we matched the following concepts: sense of belonging/inclusion; communication; emotional support; feeling accepted by others as a person; companionship; and practical support. We identified a new concept: support from friends/family in remaining healthy. Focus groups (n = 23) prioritized emotional support, communication, and support to remain healthy. Cognitive interviews (n = 30) found items were well-understood. The final 8-item measure performed well with patients (n = 708), with good construct validity. We used an Item Response Theory program to create a 3-item Short Form version of the measure, which captures 96% of patients indicating low social support. We developed the Multifactoral Assessment of Perceived Social Support (MAPSS) and Short Form (MAPSS-SF); brief, clinically relevant, sufficiently unidimensional measures of SS for use in HIV care.

8.
Ann Epidemiol ; 35: 42-47.e1, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31200987

RESUMO

PURPOSE: Depression strongly predicts stroke incidence, suggesting that treating depression may reduce stroke risk. Antidepressant medications, however, may increase stroke risk via direct pathways. Previous evidence on antidepressant medication and stroke incidence is mixed. We evaluated associations between antidepressant use and incident stroke. METHODS: For 2302 Adult Changes in Thought cohort participants with no stroke at study entry, we characterized antidepressant use from pharmacy records, biennial depressive symptoms with a 10-item Centers for Epidemiologic Study-Depression scale, and incident strokes from ICD codes. We used discrete-time survival models with inverse probability weighting to compare stroke risk associated with filling antidepressant prescriptions and by medication category: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors, or other. RESULTS: Over an average 8.4-year follow-up, 441 incident strokes occurred. Filling antidepressant medications 3+ times versus 0-2 times predicted 35% increased odds of stroke (OR = 1.35; 95% CI: 0.98, 1.66). Use of TCAs was associated with stroke onset (OR per 10 fills = 1.28; CI: 1.04, 1.57), but use of selective serotonin reuptake inhibitors (OR = 0.98; CI: 0.80, 1.20) or other antidepressants (OR = 0.99; CI: 0.67, 1.45) was not. CONCLUSIONS: Although patients who received antidepressant medication were at higher risk of stroke, this association appeared specific to TCA prescriptions.

9.
Acta Neuropathol Commun ; 7(1): 91, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174609

RESUMO

Alzheimer's disease neuropathologic change (ADNC) is defined by progressive accumulation of ß-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31063188

RESUMO

OBJECTIVE: The Automated Neuropsychological Assessment Metrics (Version 4) Traumatic Brain Injury Military (ANAM4 TBI-MIL) is commonly administered among U.S. service members both pre-deployment and following TBI. The current study used the ANAM4 TBI-MIL to develop a cognition summary score for TBI research and clinical trials, comparing eight composite scores based on their distributions and sensitivity/specificity when differentiating between service members with and without mild TBI (MTBI). METHOD: Male service members with MTBI (n = 56; Mdn = 11 days-since-injury) or no self-reported TBI history (n = 733) completed eight ANAM4 TBI-MIL tests. Their throughput scores (correct responses/minute) were used to calculate eight composite scores: the overall test battery mean (OTBM); global deficit score (GDS); neuropsychological deficit score-weighted (NDS-W); low score composite (LSC); number of scores <50th, ≤16th percentile, or ≤5th percentile; and the ANAM Composite Score (ACS). RESULTS: The OTBM and ACS were normally distributed. Other composites had skewed, zero-inflated distributions (62.9% had GDS = 0). All composites differed significantly between participants with and without MTBI (p < .001), with deficit scores showing the largest effect sizes (d = 1.32-1.47). The Area Under the Curve (AUC) was lowest for number of scores ≤5th percentile (AUC = 0.653) and highest for the LSC, OTBM, ACS, and NDS-W (AUC = 0.709-0.713). CONCLUSIONS: The ANAM4 TBI-MIL has no well-validated composite score. The current study examined multiple candidate composite scores, finding that deficit scores showed larger group differences than the OTBM, but similar AUC values. The deficit scores were highly correlated. Future studies are needed to determine whether these scores show less redundancy among participants with more severe TBIs.

11.
Circ Genom Precis Med ; 12(6): e002390, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059280

RESUMO

BACKGROUND: Antiretroviral therapy (ART) for HIV infection increases risk for coronary artery disease (CAD), presumably by causing dyslipidemia and increased atherosclerosis. We applied systems pharmacology to identify and validate specific regulatory gene networks through which ART drugs may promote CAD. METHODS: Transcriptional responses of human cell lines to 15 ART drugs retrieved from the Library of Integrated Cellular Signatures (overall 1127 experiments) were used to establish consensus ART gene/transcriptional signatures. Next, enrichments of differentially expressed genes and gene-gene connectivity within these ART-consensus signatures were sought in 30 regulatory gene networks associated with CAD and CAD-related phenotypes in the Stockholm Atherosclerosis Gene Expression study. RESULTS: Ten of 15 ART signatures were significantly enriched both for differential expression and connectivity in a specific atherosclerotic arterial wall regulatory gene network (AR-RGN) causal for CAD involving RNA processing genes. An atherosclerosis in vitro model of cholestryl ester-loaded foam cells was then used for experimental validation. Treatments of these foam cells with ritonavir, nelfinavir, and saquinavir at least doubled cholestryl ester accumulation ( P=0.02, 0.0009, and 0.02, respectively), whereas RNA silencing of the AR-RGN top key driver, PQBP1 (polyglutamine binding protein 1), significantly curbed cholestryl ester accumulation following treatment with any of these ART drugs by >37% ( P<0.05). CONCLUSIONS: By applying a novel systems pharmacology data analysis framework, 3 commonly used ARTs (ritonavir, nelfinavir, and saquinavir) were found altering the activity of AR-RGN, a regulatory gene network promoting foam cell formation and risk of CAD. Targeting AR-RGN or its top key driver PQBP1 may help reduce CAD side effects of these ART drugs.

12.
Pharmacotherapy ; 39(5): 530-543, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30861179

RESUMO

OBJECTIVES: To examine the association between central nervous system (CNS)-active medication use and the risk of fall-related injury in community-dwelling older adults following dementia onset. Further, to evaluate increased risk at higher doses or with a greater number of CNS-active medication classes. METHODS: Participants included community-dwelling older adults aged 65 years and older with a dementia diagnosis participating in the Adult Changes in Thought Study. From automated pharmacy data, a time-varying composite measure of CNS-active medication use was created. Central nervous system-active medication use was classified as current (use within prior 30 days), recent (prior 31-90 days), past (prior 91-365 days), and nonuse (no exposure in prior year). For current users, standardized daily doses (SDDs) were calculated for each CNS-active medication and summed across medications, and the number of CNS-active medication classes used was also measured. The outcome was fall-related injury based on emergency department, inpatient, and outpatient International Classification of Diseases, Ninth Revision (ICD-9) and external cause of injury (E) codes. RESULTS: Among 793 subjects, 303 fall-related injuries occurred over a mean follow-up of 3.7 years (2907 total person-years). Relative to nonuse, fall risk was significantly higher for current use (adjusted hazard ratio [HR] 1.59, 95% confidence internal [CI] 1.19-2.12) but not for past or recent use. Among current users, increased risk was seen across SDD levels: HRs (95% CI): 1.77 (1.19-2.62), 1.79 (1.25-2.56), and 1.35 (0.96-1.92) for less than 1 SDD, 1 to less than 2 SDDs, and 2 or more SDDs, respectively (trend test, p=0.14). A trend was seen for increasing risk with a greater number of CNS-active medication classes; however, this was not statistically significant (trend test, p=0.084). CONCLUSIONS: Current use of CNS-active medications was associated with fall-related injury in community-dwelling older adults followed from time of dementia onset, with increased risk even with use of low doses.

13.
J Alzheimers Dis ; 68(2): 647-655, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883356

RESUMO

BACKGROUND: The aging eye offers unique opportunities to study and understand the aging brain, in particular related to Alzheimer's disease (AD) and dementia. However, little is known about relationships between eye diseases and dementia-related neurodegeneration. OBJECTIVE: To determine the potential association between three age-related eye diseases and AD and dementia-related neuropathology. METHODS: We reviewed autopsy data from the prospective longitudinal Adult Changes in Thought (ACT) cohort. ICD-9 codes were used to identify diagnoses of diabetic retinopathy, glaucoma, and age-related macular degeneration. Multivariate regression models were used to determine odds ratios (OR) of neuropathology features associated with dementia, including Braak stage, Consortium to Establish a Registry for AD (CERAD score), Lewy bodies, hippocampal sclerosis, and microvascular brain injury, in addition to quantitative paired helical filament (PHF)-tau levels for people with and without each eye condition. We also evaluated interactions between eye conditions and dementia related neuropathologic findings were evaluated. RESULTS: 676 autopsies were included. Diabetic retinopathy was significantly associated with increased risk of deep cerebral microinfarcts (OR = 1.91 [95% confidence interval (CI) 1.11, 3.27], p = 0.02). No other significant association or interaction between eye diseases and neuropathology was found. When PHF-tau quantity was evaluated in 124 decedents, the OR for the association between PHF-tau in the occipital cortex and glaucoma was 1.36 (95% CI 0.91, 2.03, p = 0.13). No statistical correction was made for multiple comparisons. CONCLUSION: Increased risk of deep cerebral microinfarcts was found in participants diagnosed with diabetic retinopathy. Eye diseases such as glaucoma may increase susceptibility to neurofibrillary tangles in the occipital cortex.

14.
J Alzheimers Dis ; 68(4): 1439-1451, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909213

RESUMO

Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed = 5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant's mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI prevalence ranged from 56-92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk.

15.
J Alzheimers Dis ; 68(2): 523-529, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814348

RESUMO

We administered a mixed-method survey to 1,661 patients in a large health system to assess preferences toward antihypertensive use for dementia prevention. If a specific antihypertensive medication was shown to prevent or delay dementia, the vast majority (>90%) of respondents currently taking an antihypertensive reported that they would be willing to take that specific antihypertensive starting as early as mid-life. Concerns reported were potential side effects, lack of evidence of effectiveness, blood pressure being normal or low, and medication cost. Analysis of free-text responses revealed themes of concerns regarding evidence of effectiveness and health priorities.

16.
J Alzheimers Dis ; 68(3): 1071-1083, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909217

RESUMO

BACKGROUND: Past research has focused on risk factors for developing dementia, with increasing recognition of "resilient" people who live to old age with intact cognitive function despite pathological features of Alzheimer's disease (AD). OBJECTIVE: To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology. METHODS: We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores ≥86 within two years of death and no clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors. RESULTS: We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01-3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09-0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15-0.78). CONCLUSION: Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience.

18.
Health Serv Res ; 54(4): 773-781, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30868557

RESUMO

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.

19.
Nat Genet ; 51(3): 568-576, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804563

RESUMO

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.


Assuntos
Transcriptoma/genética , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética
20.
BMC Geriatr ; 19(1): 41, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764775

RESUMO

BACKGROUND: Detecting patients with undiagnosed dementia is an important clinical challenge. Changes in medication adherence might represent an early sign of cognitive impairment. We sought to examine antihypertensive and statin adherence trajectories in community-dwelling older adults, comparing people who went on to develop dementia to those who did not. METHODS: We analyzed data from Adult Changes in Thought (ACT), a population-based cohort study embedded within an integrated healthcare delivery system. Analyses included 4368 participants aged ≥65 years who had at least one follow-up visit. Research-quality dementia diagnoses were used to identify cases. We selected non-dementia control visits matched on age, sex, and study cohort that occurred at similar ACT follow-up time as the case's dementia onset; we treated this as the index date. Participants were included if they were prevalent users of either a statin or antihypertensive medication on the first day of follow up - 3 years prior to the index date. Using prescription fill dates and days supply, we calculated daily binary medication availability measures for each participant ('days covered') over 3 years leading up to the index date. We used group-based trajectory models to identify patterns of antihypertensive and statin adherence, and used conditional logistic regression to examine associations between adherence trajectories and dementia. RESULTS: Four trajectories were identified for antihypertensive users (292 cases, 3890 control visits), including near perfect (n = 1877, 36.6% cases, 45.5% controls), high (n = 1840, 43.2% cases, 44.1% controls), moderate (n = 365, 18.5% cases, 8.0% controls) and early poor adherence (n = 100, 1.7% cases, 2.4% controls). Odds of dementia was 3 times greater for those with moderate antihypertensive adherence compared to those with near perfect adherence (adjusted OR 3.0, 95% CI 2.0, 4.3). Four trajectories were identified for statin users (148 cases, 1131 control visits), including high (n = 1004, 75.0% cases, 79.0% controls), moderate (n = 192, 19.6% cases, 14.4% controls), early poor (n = 43, 2.0% cases, 3.5% controls), and delayed poor adherence (n = 40, 3.4% cases, 3.1% controls). No association was detected between statin adherence trajectories and dementia. CONCLUSIONS: Patterns of medication adherence may be useful to identify a subset of people at higher likelihood of developing dementia.

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