Publications by authors named "Janet Johnston"

84 Publications

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

A Formative Evaluation of Two FASD Prevention Communication Strategies.

Alcohol Alcohol 2018 Jul;53(4):461-469

Institute for Circumpolar Health Studies, College of Health at the University of Alaska Anchorage, 1901 Bragaw Street, Suite 270, Anchorage, AK, USA.

Aims: To evaluate the feasibility, acceptability and effectiveness of placing FASD prevention messages in the women's restrooms of establishments serving alcohol in Alaska and the Yukon, regions with high rates of FASD.

Methods: Our team placed an FASD educational poster, and posters affixed to a pregnancy test dispenser, in women's restrooms of bars and restaurants. We compared drinking behaviors and knowledge and beliefs about FASD among participants at baseline and at follow-up.

Results: Respondents consisted of 2132 women who completed a baseline survey and 1182 women who completed both a baseline and a follow-up survey. Women in both groups showed improvement in knowledge of FASD; the dispenser group scored higher than participants in the poster group on the FASD Health Belief questions at both baseline and follow-up. Forty-three women learned they were pregnant from our pregnancy tests and alcohol consumption among pregnant women was lower at follow-up than at baseline.

Conclusions: FASD prevention messages, particularly paired with pregnancy test dispensers, in the women's restrooms of establishments that serve alcohol can effectively promote informed alcohol consumption decisions among women who are, or may become, pregnant.

Short Summary: In this FASD prevention feasibility study, we found that FASD prevention messages, particularly paired with pregnancy test dispensers, placed in the women's restrooms of establishments that serve alcohol can effectively promote informed alcohol consumption decisions among women who are, or may become, pregnant.
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http://dx.doi.org/10.1093/alcalc/agx122DOI Listing
July 2018

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Nat Genet 2017 09 17;49(9):1373-1384. Epub 2017 Jul 17.

Boston University School of Medicine, Boston, Massachusetts, USA.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10, odds ratio (OR) = 0.68, minor allele frequency (MAF) = 0.0059, MAF = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10, OR = 1.43, MAF = 0.011, MAF = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10, OR = 1.67, MAF = 0.0143, MAF = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
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http://dx.doi.org/10.1038/ng.3916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669039PMC
September 2017

Prevalence of Mixed Connective Tissue Disease in a Population-Based Registry of American Indian/Alaska Native People in 2007.

Arthritis Care Res (Hoboken) 2017 08 10;69(8):1271-1275. Epub 2017 Jul 10.

Emory University, Atlanta, Georgia.

Objective: To determine the prevalence of mixed connective tissue disease (MCTD) in 2007 in the Indian Health Service (IHS) active clinical population from 3 regions of the US.

Methods: The IHS Lupus Registry was designed to identify possible MCTD cases in addition to systemic lupus erythematosus cases. The population denominator for this report includes American Indian or Alaska Native adults within the IHS active clinical population in 2007, residing in select communities in 3 regions of the US. Potential MCTD cases were identified using a broad range of diagnostic codes and were confirmed by detailed medical record abstraction. Classification as MCTD for this analysis required both rheumatologist diagnosis of MCTD without diagnosis of other CTD, and documentation of the Alarcón-Segovia MCTD criteria in the medical record. Prevalence was also calculated using 2 alternate definitions of MCTD.

Results: The age-adjusted prevalence of MCTD using our primary definition was 6.4 per 100,000 (95% confidence interval 2.8-12.8). The prevalence was higher in women than in men using all 3 definitions of MCTD, and no men met the criteria for the primary definition of MCTD.

Conclusion: The first population-based estimates of the prevalence of MCTD in the US American Indian/Alaska Native population show that the prevalence appears to be higher than in other populations. Additional population-based estimates are needed to better understand the epidemiology of MCTD.
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http://dx.doi.org/10.1002/acr.23135DOI Listing
August 2017

Platelet Membrane β-Secretase Activity in Mild Cognitive Impairment and Conversion to Dementia: a Longitudinal Study.

J Alzheimers Dis 2016 ;49(4):1095-103

A blood-based biomarker to complement the clinical and neuropsychological assessments used to evaluate the risk of individuals with mild cognitive impairment (MCI) developing Alzheimer's disease (AD) would be invaluable. Previous pilot studies by our group identified elevated platelet membrane β-secretase activity in patients with AD and MCI, as compared to controls, and this activity was influenced by membrane cholesterol levels. The present study investigated baseline platelet membrane β-secretase activity and cholesterol levels in 97 MCI participants and 85 controls and explored whether these parameters differed in individuals with stable MCI, as compared to those who subsequently developed AD. To evaluate signal specificity, β-secretase activity assays were conducted in the presence and absence of beta-site amyloid-β protein precursor-cleaving enzyme (BACE) inhibitors. Baseline platelet membrane β-secretase activity did not differ significantly in MCI participants, as compared to controls, and platelet membrane cholesterol levels were significantly lower in the MCI group. The longitudinal study indicated that the activities inhibited by two different BACE inhibitors did not predict conversion to AD; however, the activity that was not affected by BACE inhibitors was significantly (40%) higher in individuals with stable MCI, as compared with those who subsequently developed AD. These findings indicated that further research into the source of this activity could contribute to a measure facilitating prediction of the risk of conversion from MCI to AD.
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http://dx.doi.org/10.3233/JAD-150795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927817PMC
October 2016

Untargeted metabolomic analysis of human plasma indicates differentially affected polyamine and L-arginine metabolism in mild cognitive impairment subjects converting to Alzheimer's disease.

PLoS One 2015 24;10(3):e0119452. Epub 2015 Mar 24.

Advanced Asset Technology Centre, Institute for Global Food Security, Queen's University Belfast, Stranmillis Road, Belfast, BT9 5AG, United Kingdom.

This study combined high resolution mass spectrometry (HRMS), advanced chemometrics and pathway enrichment analysis to analyse the blood metabolome of patients attending the memory clinic: cases of mild cognitive impairment (MCI; n = 16), cases of MCI who upon subsequent follow-up developed Alzheimer's disease (MCI_AD; n = 19), and healthy age-matched controls (Ctrl; n = 37). Plasma was extracted in acetonitrile and applied to an Acquity UPLC HILIC (1.7μm x 2.1 x 100 mm) column coupled to a Xevo G2 QTof mass spectrometer using a previously optimised method. Data comprising 6751 spectral features were used to build an OPLS-DA statistical model capable of accurately distinguishing Ctrl, MCI and MCI_AD. The model accurately distinguished (R2 = 99.1%; Q2 = 97%) those MCI patients who later went on to develop AD. S-plots were used to shortlist ions of interest which were responsible for explaining the maximum amount of variation between patient groups. Metabolite database searching and pathway enrichment analysis indicated disturbances in 22 biochemical pathways, and excitingly it discovered two interlinked areas of metabolism (polyamine metabolism and L-Arginine metabolism) were differentially disrupted in this well-defined clinical cohort. The optimised untargeted HRMS methods described herein not only demonstrate that it is possible to distinguish these pathologies in human blood but also that MCI patients 'at risk' from AD could be predicted up to 2 years earlier than conventional clinical diagnosis. Blood-based metabolite profiling of plasma from memory clinic patients is a novel and feasible approach in improving MCI and AD diagnosis and, refining clinical trials through better patient stratification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0119452PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372431PMC
April 2016

Hand-assisted laparoscopic repair of a grade IV rectal tear in a postparturient mare.

J Am Vet Med Assoc 2014 Oct;245(7):816-20

Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348.

Case Description: An 8-year-old multiparous Thoroughbred broodmare was admitted for evaluation of a rectal tear sustained during parturition.

Clinical Findings: On initial evaluation, the mare had mild signs of abdominal discomfort. A full-thickness rectal tear located 30 cm cranial to the anus and extending approximately 15 cm longitudinally along the surface of the small colon between the 4 and 6 o'clock positions, when viewed from behind, was diagnosed on examination per rectum.

Treatment And Outcome: Laparoscopic evaluation of the abdomen was performed to assess the tear and extent of peritoneal contamination. A hand-assisted repair via a flank incision was performed. The tear was closed in a single-layer, simple continuous pattern with size-0 polydioxanone with a handheld needle holder. Subsequently, a ventral midline celiotomy was performed, and intestinal contents were evacuated via a pelvic flexure enterotomy and a typhlotomy. Following surgery, the mare was managed with IV fluid therapy, partial parenteral nutrition, antimicrobials, and NSAIDs for 5 to 7 days before being gradually reintroduced to a complete pelleted feed and alfalfa hay. Prior to discharge, examination per rectum revealed no stricture formation associated with repair. The mare was discharged from the hospital and performed successfully as a broodmare, with the delivery of a live foal 1 year after surgery.

Clinical Relevance: Successful repair with an excellent outcome was achieved in this mare. Hand-assisted laparoscopic repair should be considered as a possible treatment option in horses with grade IV rectal tears.
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http://dx.doi.org/10.2460/javma.245.7.816DOI Listing
October 2014

Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease.

Neurobiol Aging 2014 Dec 24;35(12):2883.e3-2883.e10. Epub 2014 Jul 24.

King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.

Although epidemiological studies suggest that type 2 diabetes mellitus (T2DM) increases the risk of late-onset Alzheimer's disease (LOAD), the biological basis of this relationship is not well understood. The aim of this study was to examine the genetic comorbidity between the 2 disorders and to investigate whether genetic liability to T2DM, estimated by a genotype risk scores based on T2DM associated loci, is associated with increased risk of LOAD. This study was performed in 2 stages. In stage 1, we combined genotypes for the top 15 T2DM-associated polymorphisms drawn from approximately 3000 individuals (1349 cases and 1351 control subjects) with extracted and/or imputed data from 6 genome-wide studies (>10,000 individuals; 4507 cases, 2183 controls, 4989 population controls) to form a genotype risk score and examined if this was associated with increased LOAD risk in a combined meta-analysis. In stage 2, we investigated the association of LOAD with an expanded T2DM score made of 45 well-established variants drawn from the 6 genome-wide studies. Results were combined in a meta-analysis. Both stage 1 and stage 2 T2DM risk scores were not associated with LOAD risk (odds ratio = 0.988; 95% confidence interval, 0.972-1.004; p = 0.144 and odds ratio = 0.993; 95% confidence interval, 0.983-1.003; p = 0.149 per allele, respectively). Contrary to expectation, genotype risk scores based on established T2DM candidates were not associated with increased risk of LOAD. The observed epidemiological associations between T2DM and LOAD could therefore be a consequence of secondary disease processes, pleiotropic mechanisms, and/or common environmental risk factors. Future work should focus on well-characterized longitudinal cohorts with extensive phenotypic and genetic data relevant to both LOAD and T2DM.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.07.023DOI Listing
December 2014

Medical home implementation and trends in diabetes quality measures for AN/AI primary care patients.

Prim Care Diabetes 2015 Apr 2;9(2):120-6. Epub 2014 Aug 2.

Institute for Circumpolar Health Studies, University of Alaska Anchorage, 3211 Providence Drive DPL 404, Anchorage, AK 99508, USA.

Aims: Patient-centered medical home (PCMH) principles including provider continuity, coordination of care, and advanced access align with healthcare needs of patients with Type II diabetes mellitus (DM-II). We investigate changes in trend for DM-II quality indicators after PCMH implementation at Southcentral Foundation, a tribal health organization in Alaska.

Methods: Monthly rates of DM-II incidence, hemoglobin A1c (HbA1c) measurements, and service utilization were calculated from electronic health records from 1996 to 2009. We performed interrupted time series analysis to estimate changes in trend.

Results: Rates of new DM-II diagnoses were stable prior to (p=0.349) and increased after implementation (p<0.001). DM-II rates of HbA1c screening increased, though not significantly, before (p=0.058) and remained stable after implementation (p=0.969). There was non-significant increasing trend in both periods for percent with average HbA1c less than 7% (53 mmol/mol; p=0.154 and p=0.687, respectively). Number of emergency visits increased before (p<0.001) and decreased after implementation (p<0.001). Number of inpatient days decreased in both periods, but not significantly (p=0.058 and p=0.101, respectively).

Conclusions: We found positive changes in DM-II quality trends following PCMH implementation of varying strength and onset of change, as well as duration of sustained trend.
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http://dx.doi.org/10.1016/j.pcd.2014.06.005DOI Listing
April 2015

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

PLoS One 2014 12;9(6):e94661. Epub 2014 Jun 12.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.

Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci.

Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094661PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055488PMC
October 2015

Prevalence and incidence of systemic lupus erythematosus in a population-based registry of American Indian and Alaska Native people, 2007-2009.

Arthritis Rheumatol 2014 Sep;66(9):2494-502

Alaska Native Tribal Health Consortium, Anchorage.

Objective: Few studies have investigated the epidemiology of systemic lupus erythematosus (SLE) in American Indian and Alaska Native populations. The objective of this study was to determine the prevalence and incidence of SLE in the Indian Health Service (IHS) active clinical population in 3 regions of the US.

Methods: For this population-based registry within the IHS, the denominator consisted of individuals in the IHS active clinical population in 2007, 2008, and/or 2009 and residing in a community in 1 of 3 specified regions. Potential SLE cases were identified based on the presence of a diagnostic code for SLE or related disorder in the IHS National Data Warehouse. Detailed medical record abstraction was performed for each potential case. The primary case definition was documentation in the medical record of ≥4 of the revised American College of Rheumatology criteria for the classification of SLE. Prevalence was calculated for 2007, and the mean annual incidence was calculated for the years 2007 through 2009.

Results: The age-adjusted prevalence and incidence of SLE according to the primary definition were 178 per 100,000 person-years (95% confidence interval [95% CI] 157-200) and 7.4 per 100,000 person-years (95% CI 5.1-10.4). Among women, the age-adjusted prevalence was 271, and the age-adjusted incidence was 10.4. The prevalence was highest in women ages 50-59 years and in the Phoenix Area IHS.

Conclusion: The first population-based lupus registry in the US American Indian and Alaska Native population has demonstrated that the prevalence and incidence of SLE are high. Our estimates are as high as or higher than the rates reported in the US black population.
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http://dx.doi.org/10.1002/art.38720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617772PMC
September 2014

Plasma clusterin levels and the rs11136000 genotype in individuals with mild cognitive impairment and Alzheimer's disease.

Curr Alzheimer Res 2013 Nov;10(9):973-8

Centre for Public Health, Queen's University Belfast, Institute of Pathology, Grosvenor Road, Belfast BT12 6BJ, Northern. Ireland.

Aim: Substantial evidence links atherosclerosis and Alzheimer's disease (AD). Apolipoproteins, such as apolipoprotein E, have a causal relationship with both diseases. The rs11136000 SNP within the CLU gene, which encodes clusterin (apolipoprotein J), is also associated with increased AD risk. The aim of this study was to investigate the relationship between plasma clusterin and the rs11136000 genotype in mild cognitive impairment (MCI) and AD.

Methods: Plasma and DNA samples were collected from control, MCI and AD subjects (n=142, 111, 154, respectively). Plasma clusterin was determined by ELISA and DNA samples were genotyped for rs11136000 by TaqMan assay.

Results: Plasma clusterin levels were higher in MCI and AD subjects vs. controls (222.3 ± 61.3 and 193.6 ± 58.2 vs. 178.6 ± 52.3 μg/ml, respectively; p<0.001 for both comparisons), and in MCI vs. AD (p<0.05). Plasma clusterin was not influenced by genotype in the MCI and AD subjects, although in control subjects plasma clusterin was lower in the TT vs. TC genotypes (157.6 ± 53.4 vs. 188.6 ± 30.5 μg/ml; p<0.05).

Conclusion: This study examined control, MCI and AD subjects, identifying for the first time that plasma clusterin levels were influenced, not only by the presence of AD, but also the transitional stage of MCI, while rs11136000 genotype only influenced plasma clusterin levels in the control group. The increase in plasma clusterin in MCI and AD subjects may occur in response to the disease process and would be predicted to increase binding capacity for amyloid-beta peptides in plasma, enhancing their removal from the brain.
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http://dx.doi.org/10.2174/15672050113106660162DOI Listing
November 2013

Initial findings from the implementation of a community-based sentinel surveillance system to assess the health effects of climate change in Alaska.

Int J Circumpolar Health 2013 5;72. Epub 2013 Aug 5.

Institute for Circumpolar Health Studies, University of Alaska, Anchorage, AK, USA.

Background: This report describes the results of a study to determine whether a community-based sentinel surveillance system can be developed and implemented to assess the health effects of climate change, and to contribute to local discussions to mitigate these health effects. The purpose of this report is to describe the process and outcomes of this innovative approach to identifying priority areas for adaptation investment. This report can be used to assist local, state and federal governments in determining how to develop actions and policies to promote adaptation to climate change.

Objective: To evaluate the health effects of climate change in rural Alaska.

Design: We conducted an iterative and participatory process to develop metrics, an instrument and a protocol to collect sentinel surveillance data on the health effects of climate change in 3 ecologically distinct regions of the state.

Results: We collected surveillance data from 91 study participants over the course of 12 months. These data were analyzed and categorized by frequency and association between specific health outcomes or health-related factors (such as food security) and reported exposure to environmental effects of climate change. We found significant associations between several health outcomes and health outcome mediators and reported exposures. We presented these data to study participants in community settings and moderated discussions of likely causal factors for these measured associations, and helped community residents to identify specific adaption measures to mitigate those health effects.

Conclusions: We conclude that community-based sentinel surveillance is an effective method for assessing health outcomes from exposure to environmental effects of climate change, and informing climate change health adaptation planning in Alaskan communities. We contend that it would be effective in other regions of the nation as well.
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http://dx.doi.org/10.3402/ijch.v72i0.21405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754612PMC
August 2014

Tribal implementation of a patient-centred medical home model in Alaska accompanied by decreased hospital use.

Int J Circumpolar Health 2013 5;72. Epub 2013 Aug 5.

Institute for Circumpolar Health Studies, University of Alaska Anchorage, Anchorage, AK 99508, USA.

Background: Between 1995 and 1998, tribally owned Southcentral Foundation (SCF) incrementally assumed responsibility from the Indian Health Service (IHS) for primary care services on the Alaska Native Medical Center (ANMC) campus in Anchorage, Alaska. In 1999, SCF began implementing components of a Patient-Centered Medical Home (PCMH) model to improve access and continuity of care.

Objective: To evaluate hospitalisation trends before, during and after PCMH implementation.

Design: Time series analysis of aggregated medical record data.

Methods: Regression analysis with correlated errors was used to estimate trends over time for the percent of customer-owners hospitalised overall and for specific conditions during 4 time periods (March 1996-July 1999: SCF assumes responsibility for primary care; August 1999-July 2000: PCMH implementation starts; August 2000-April 2005: early post-PCMH implementation; May 2005-December 2009: later post-PCMH implementation). Analysis was restricted to individuals residing in Southcentral Alaska and receiving health care at ANMC.

Results: The percent of SCF customer-owners hospitalised per month for any reason was steady before and during PCMH implementation, declined steadily immediately following implementation and subsequently stabilised. The percent hospitalised per month for unintentional injury or poisoning also declined during and after the PCMH implementation. Among adult asthma patients, the percent hospitalised annually for asthma declined prior to and during implementation and remained lower thereafter. The percent of heart failure patients hospitalised annually for heart failure remained relatively constant throughout the study period while the percent of hypertension patients hospitalised for hypertension shifted higher between 1999 and 2002 compared to earlier and later years.

Conclusion: Implementation of PCMH at SCF was accompanied by decreases in the percent of customer-owners hospitalised monthly for any reason and for unintentional injury and in the percent of asthma patients hospitalised annually for asthma. Increased accessibility to empanelled care teams may have contributed to decreased need for hospitalisation.
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http://dx.doi.org/10.3402/ijch.v72i0.20960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753131PMC
August 2014

Process and outcomes of patient-centered medical care with Alaska Native people at Southcentral Foundation.

Ann Fam Med 2013 May-Jun;11 Suppl 1:S41-9

Institute for Circumpolar Health Studies, University of Alaska Anchorage, 3211 Providence Dr, DPL 404, Anchorage, AK 99508, USA.

Purpose: This study describes key elements of the transition to a patient-centered medical home (PCMH) model at Southcentral Foundation (SCF), a tribally owned and managed primary care system, and evaluates changes in emergency care use for any reason, for asthma, and for unintentional injuries, during and after the transition.

Methods: We conducted a time series analyses of emergency care use from medical record data. We also conducted 45 individual, in-depth interviews with PCMH patients (customer-owners), primary care clinicians, health system employees, and tribal leaders.

Results: Emergency care use for all causes was increasing before the PCMH implementation, dropped during and immediately after the implementation, and subsequently leveled off. Emergency care use for adult asthma dropped before, during, and immediately after implementation, subsequently leveling off approximately 5 years after implementation. Emergency care use for unintentional injuries, a comparison variable, showed an increasing trend before and during implementation and decreasing trends after implementation. Interview participants observed improved access to primary care services after the transition to the PCMH tempered by increased staff fatigue. Additional themes of PCMH transformation included the building of relationships for coordinated, team-based care, and the important role of leadership in PCMH implementation.

Conclusions: All reported measures of emergency care use show a decreasing trend after the PCMH implementation. Before the implementation, overall use and use for unintentional injuries had been increasing. The combined quantitative and qualitative results are consistent with decreased emergency care use resulting from a decreased need for emergency care services due to increased availability of primary care services and same-day appointments.
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http://dx.doi.org/10.1370/afm.1474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707246PMC
October 2013

The development of effective biomarkers for Alzheimer's disease: a review.

Int J Geriatr Psychiatry 2013 Apr 4;28(4):331-40. Epub 2012 Jun 4.

Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.

Objective: There is a widely recognised need to develop effective Alzheimer's disease (AD) biomarkers to aid the development of disease-modifying treatments, to facilitate early diagnosis and to improve clinical care. This overview aims to summarise the utility of key neuroimaging and cerebrospinal fluid (CSF) biomarkers for AD, before focusing on the latest efforts to identify informative blood biomarkers.

Design: A literature search was performed using PubMed up to September 2011 for reviews and primary research studies of neuroimaging (magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and amyloid imaging), CSF and blood-based (plasma, serum and platelet) biomarkers in AD and mild cognitive impairment. Citations within individual articles were examined to identify additional studies relevant to this review.

Results: Evidence of AD biomarker potential was available for imaging techniques reflecting amyloid burden and neurodegeneration. Several CSF measures are promising, including 42 amino acid β-amyloid peptide (Aβ42 ); total tau (T-tau) protein, reflecting axonal damage; and phosphorylated tau (P-tau), reflecting neurofibrillary tangle pathology. Studies of plasma Aβ have produced inferior diagnostic discrimination. Alternative plasma and platelet measures are described, which represent potential avenues for future research.

Conclusions: Several imaging and CSF markers demonstrate utility in predicting AD progression and determining aetiology. These require standardisation before forming core elements of diagnostic criteria. The enormous potential available for identifying a minimally-invasive, easily-accessible blood measure as an effective AD biomarker currently remains unfulfilled.
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http://dx.doi.org/10.1002/gps.3829DOI Listing
April 2013

Reproductive cancer risk factors among Alaska Native women: the Alaska Education and Research Towards Health (EARTH) Study.

Womens Health Issues 2012 Jul-Aug;22(4):e387-93. Epub 2012 May 18.

Alaska Native Tribal Health Consortium, Anchorage, Alaska 99508, USA.

Background: The purpose of this study was to provide estimates for the prevalence of reproductive cancer risk factors among Alaska Native (AN) women who enrolled in the Alaska Education and Research Towards Health (EARTH) Study from 2004 to 2006.

Methods: A total of 2,315 AN women 18 years or older completed reproductive health questions as part of a comprehensive health history questionnaire. The reproductive health section included menstrual status (age at menarche and menopause), pregnancy and live birth history, use of hormonal contraception, hormone replacement therapy, and history of hysterectomy and/or oophorectomy.

Results: A total of 463 (20%) of women experienced menarche before age 12 with a decline in mean age at menarche by age cohort. More than 86% had been pregnant (mean number of pregnancies, 3.8; mean number of live births, 2.9). More than one half of women (58%) had their first live birth between the ages of 18 and 24. Almost 28% of participants had completed menopause, of whom 24% completed menopause after age 52. Fewer than half (43%) reported ever using hormone replacement therapy. Almost two thirds (62%) reported ever using oral contraceptives, and fewer reported ever using birth control shots (30%) or implants (10%).

Conclusions: This study is unique in reporting reproductive health factors among a large group of AN women. These data show that AN women have selective protective factors for reproductive cancers, including low nulliparity rates, low use of menopausal estrogens, and common use of contraceptive hormones. However, analysis by age cohorts indicates decreasing age at menarche that might increase the risk for reproductive cancers among AN women in the future.
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http://dx.doi.org/10.1016/j.whi.2012.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569005PMC
September 2012

α-Synuclein mRNA and soluble α-synuclein protein levels in post-mortem brain from patients with Parkinson's disease, dementia with Lewy bodies, and Alzheimer's disease.

Brain Res 2012 Jun 17;1459:71-80. Epub 2012 Apr 17.

Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, N. Ireland, UK.

α-Synuclein is a neuronal protein implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Whilst increased α-synuclein expression due to gene duplication or triplication can cause familial PD, previous studies of α-synuclein levels in idiopathic disease have produced conflicting data. We quantified α-synuclein mRNA and soluble protein in five human post-mortem brain regions from four groups of individuals with PD, DLB, Alzheimer's disease (AD) and matched controls. α-Synuclein mRNA levels, measured using quantitative real-time PCR, did not differ significantly between groups in any brain regions examined. In contrast, levels of soluble α-synuclein protein, measured by ELISA, were significantly lower in 4 of the 5 regions for patients with DLB, and in 2 of the 5 regions for patients with PD, compared to controls. Soluble α-synuclein protein levels were not significantly different in the AD patients, compared to controls, in 4 of the 5 regions. This study indicates that although levels of soluble α-synuclein protein are lower in DLB and PD, there is no evidence for a corresponding decrease in α-synuclein mRNA levels. This might result from altered translation, or removal of α-synuclein protein from a soluble detectable state, either by turnover or conversion to an insoluble form.
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http://dx.doi.org/10.1016/j.brainres.2012.04.018DOI Listing
June 2012

Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk.

Int J Mol Epidemiol Genet 2012 5;3(1):30-8. Epub 2012 Feb 5.

Dementia Research Group, University of Bristol, Institute of Clinical Neurosciences, Frenchay Hospital, Bristol, UK.

Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important β-amyloid (Aβ)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aβ accumulation in frontal cortex - levels of total soluble Aβ, oligomeric Aβ(1-42), and guanidine-extractable (insoluble) Aβ - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aβ levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316445PMC
May 2012

Zinc transporter mRNA levels in Alzheimer's disease postmortem brain.

J Alzheimers Dis 2012 ;29(4):863-73

Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, N. Ireland.

Zinc (Zn2+) is concentrated into pre-synaptic vesicles and co-released with neurotransmitter at some synapses. Zn2+ can accelerate assembly of the amyloid-β peptides (Aβ) and tau protein central to the neuropathological changes found in Alzheimer's disease (AD). Altered protein levels of the membrane Zn2+ transporters ZnT1, ZnT4, and ZnT6 have been reported in AD postmortem brain tissue. The present study analyzed mRNA levels of five established (LIV1, ZIP1, ZnT1, ZnT4, and ZnT6) and one potential (PRNP) Zn2+ transporter in human postmortem brain tissue from Braak-staged individuals with AD and controls using quantitative real-time PCR. Four cortical regions (middle temporal gyrus, superior occipital gyrus, superior parietal gyrus, and superior frontal gyrus) and cerebellum were examined. PRNP mRNA levels were decreased by ∼30% in all four cortical regions examined in AD patients, but unchanged in the cerebellum. In contrast, some increases in mRNA levels of the other more established Zn2+ transporters (LIV1, ZIP1, ZnT1, ZnT6) were found in AD cortex. The ratios of the mRNA levels of LIV1, ZIP1, ZnT1, ZnT4, and ZnT6/mRNA level of neuron specific enolase increased significantly as the disease progressed and Braak stage increased. Significant correlations were also identified between mRNA levels of several of the Zn2+ transporters investigated. These expression changes could either reflect or cause the altered cortical Zn2+ distribution in AD, potentially increasing the likelihood of interactions between Zn2+ and Aβ or tau protein.
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http://dx.doi.org/10.3233/JAD-2012-112105DOI Listing
August 2012

The role of variation at AβPP, PSEN1, PSEN2, and MAPT in late onset Alzheimer's disease.

J Alzheimers Dis 2012 ;28(2):377-87

MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.

Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
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http://dx.doi.org/10.3233/JAD-2011-110824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118466PMC
May 2012

No evidence that extended tracts of homozygosity are associated with Alzheimer's disease.

Am J Med Genet B Neuropsychiatr Genet 2011 Dec 2;156B(7):764-71. Epub 2011 Aug 2.

MRC Centre for Neuropyschiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Cardiff University, Heath Park.

We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease.
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http://dx.doi.org/10.1002/ajmg.b.31216DOI Listing
December 2011

Vstm3 is a member of the CD28 family and an important modulator of T-cell function.

Eur J Immunol 2011 Apr 18;41(4):902-15. Epub 2011 Mar 18.

Department of Immunology, ZymoGenetics, Inc., Seattle, WA, USA.

Members of the CD28 family play important roles in regulating T-cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and Tregs. The nectin-family proteins CD155 and CD112 serve as counter-structures for VSTM3, and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well-characterized CD28-CTLA-4-CD80-CD86 network. In the same way that soluble CTLA-4 can be used to block T-cell responses, we show that soluble Vstm3 attenuates T-cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T-cell responses.
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http://dx.doi.org/10.1002/eji.201041136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733993PMC
April 2011

Heart disease mortality among Alaska Native people, 1981-2007.

Public Health Rep 2011 Jan-Feb;126(1):73-83

Department of Health Sciences, University of Alaska Anchorage, 4500 Diplomacy Dr., Anchorage, AK 99508, USA.

Objectives: Historically, Alaska Native (AN) people have exhibited low overall rates of heart disease mortality compared with the U.S. white (USW) population. We compared AN and USW heart disease mortality rates during the 27-year period from 1981 through 2007.

Methods: We compared AN and USW heart disease mortality rates overall and by gender, age, and disease subtype. We calculated age-adjusted rates for AN people for three nine-year periods from 1981 through 2007 and compared them with the rates for USW people.

Results: AN people > or = 35 years of age had a significantly lower rate of heart disease mortality compared with their USW counterparts (rate ratio [RR] = 0.80). The lower overall RR was due primarily to a lower ischemic heart disease mortality RR (RR = 0.63). Overall heart disease mortality decreased during the 27-year study period for both the AN (33.1%) and USW (35.0%) populations. However, hypertensive heart disease mortality increased 155.2% for AN people and 13.7% for USW people. Age-specific heart disease mortality was about 30.0% lower for AN people > or = 75 years of age compared with their USW counterparts, while it was virtually identical for the two racial/ethnic groups among people 35-74 years of age.

Conclusions: The age-adjusted AN heart disease mortality rate was consistently about 20.0% lower than the USW rate from 1981 through 2007, with similar RRs for men and women. However, combining all ages and all heart disease subgroups into a single, age-adjusted statistic obscures many important differences across ages and disease subtypes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001825PMC
http://dx.doi.org/10.1177/003335491112600111DOI Listing
March 2011

BACE1 mRNA expression in Alzheimer's disease postmortem brain tissue.

J Alzheimers Dis 2010 ;22(4):1111-22

Queen's University Belfast, School of Medicine, Dentistry and Biomedical Sciences, Northern Ireland.

β-site AβPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-β (Aβ) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in AD postmortem brains. Our study explored whether this was due to elevated BACE1 mRNA expression. RNA was prepared from five brain regions in three study groups: controls, individuals with AD, and another neurodegenerative disease group affected by either Parkinson's disease (PD) or dementia with Lewy bodies (DLB). BACE1 mRNA levels were measured using quantitative realtime PCR (qPCR) and analyzed by qbasePLUS using validated stably-expressed reference genes. Expression of glial and neuronal markers (glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), respectively) were also analyzed to quantify the changing activities of these cell populations in the tissue. BACE1 mRNA levels were significantly elevated in medial temporal and superior parietal gyri, compared to the PD/DLB and/or control groups. Superior frontal gryus BACE1 mRNA levels were significantly increased in the PD/DLB group, compared to AD and control groups. For the AD group, BACE1 mRNA changes were analyzed in the context of the reduced NSE mRNA, and strongly increased GFAP mRNA levels apparent as AD progressed (indicated by Braak stage). This analysis suggested that increased BACE1 mRNA expression in remaining neuronal cells may contribute to the increased BACE1 protein levels and activity found in brain regions affected by AD.
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http://dx.doi.org/10.3233/JAD-2010-101254DOI Listing
May 2011

Association of menopausal vasomotor symptoms with increased bone turnover during the menopausal transition.

J Bone Miner Res 2011 Apr;26(4):840-9

Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA.

The purpose of this study was to determine the longitudinal association between menopausal vasomotor symptoms (VMS) and urinary N-telopeptide level (NTX) according to menopausal stage. We analyzed data from 2283 participants of the Study of Women's Health Across the Nation, a longitudinal community-based cohort study of women aged 42 to 52 years at baseline. At baseline and annually through follow-up visit 8, participants provided questionnaire data, urine samples, serum samples, and anthropometric measurements. Using multivariable repeated-measures mixed models, we examined associations between annually assessed VMS frequency and annual NTX measurements. Our results show that mean adjusted NTX was 1.94 nM of bone collagen equivalents (BCE)/mM of creatinine higher among early perimenopausal women with any VMS than among early perimenopausal women with no VMS (p < .0001). Mean adjusted NTX was 2.44 nM BCE/mM of creatinine higher among late perimenopausal women with any VMS than among late perimenopausal women with no VMS (p = .03). Among premenopausal women, VMS frequency was not significantly associated with NTX level. When NTX values among women with frequent VMS (≥6 days in past 2 weeks) were expressed as percentages of NTX values among women without frequent VMS, the differences were 3% for premenopausal women, 9% for early perimenopausal women, 7% for late perimenopausal women, and 4% for postmenopausal women. Adjustment for serum follicle-stimulating hormone (FSH) level greatly reduced the magnitudes of associations between VMS and NTX level. We conclude that among early perimenopausal and late perimenopausal women, those with VMS had higher bone turnover than those without VMS. Prior to the final menstrual period, VMS may be a marker for risk of adverse bone health.
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http://dx.doi.org/10.1002/jbmr.259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179323PMC
April 2011

Chronic disease risk factors among Alaska Native and American Indian people, Alaska, 2004-2006.

Prev Chronic Dis 2010 Jul 15;7(4):A85. Epub 2010 Jun 15.

Alaska Native Tribal Health Consortium Community Health Services, 4000 Ambassador Dr, Anchorage, AK 99508, USA.

Introduction: The Alaska Education and Research Towards Health (EARTH) Study is being conducted to determine the prevalence of clinically measured chronic disease risk factors in a large population of American Indian/Alaska Native people (AI/AN). We report these estimates and compare them with those for the overall US population, as assessed by the National Health and Nutrition Examination Survey (NHANES).

Methods: We measured blood pressure, height, weight, and fasting serum lipids and glucose in a prospective cohort of 3,822 AI/AN participants who resided in Alaska during 2004 through 2006. We categorized participants as having chronic disease risk factors if their measurements exceeded cutoffs that were determined on the basis of national recommendations. We analyzed the prevalence of risk factors by sex and age and compared the age-adjusted prevalence with 1999-2004 NHANES measurements.

Results: EARTH participants were significantly more likely than NHANES participants to be overweight or obese and to have impaired fasting glucose, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, and hypertension. The prevalence of high total cholesterol and triglycerides was not significantly different between the 2 study populations.

Conclusion: We provide baseline clinical measurements for chronic disease risk factors for a larger study sample than any previous study of AI/AN living in Alaska. The prevalence of most risk factors measured exceeded national rates. These data can be used to tailor health interventions and reduce health disparities.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901583PMC
July 2010

Reproductive hormones and obesity: 9 years of observation from the Study of Women's Health Across the Nation.

Am J Epidemiol 2010 Jun 27;171(11):1203-13. Epub 2010 Apr 27.

Department of Epidemiology, University of Pittsburgh, Pennsylvania 15261, USA.

The effect of change in reproductive hormones and menopause on incident obesity (body mass index > or =30 kg/m(2)) and severe obesity (body mass index > or =35 kg/m(2)) was evaluated over 9 years in 3,260 US women recruited in the multiethnic Study of Women's Health Across the Nation in 1996-1997. After 9 years, cumulative incidences of obesity and severe obesity reached 21.8% and 12.3%, respectively. In multivariate analysis, hormone changes, chronic health conditions, lower physical activity, race/ethnicity, and age were significantly associated with incident obesity and/or severe obesity. The odds of incident severe obesity increased with surgical menopause (odds ratio (OR) = 5.07, 95% confidence interval (CI): 2.29, 11.20; P < 0.001) and initiation of hormone therapy prior to 12 months of amenorrhea (OR = 2.94, 95% CI: 1.14, 7.58; P = 0.03). Predictors of obesity included an increase in free androgen index (OR = 1.37, 95% CI: 1.12, 1.68; P = 0.002) and a decrease in sex hormone-binding globulin (OR = 0.60, 95% CI: 0.45, 0.80; P = 0.0005). Similar results were found for severe obesity. Obesity rates varied by race, but no hormone-by-race interactions were observed. These longitudinal data demonstrate that higher androgens, lower sex hormone-binding globulin, surgical menopause, and early hormone therapy use predict incident obesity and/or severe obesity in a multiracial cohort of women transitioning into menopause.
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http://dx.doi.org/10.1093/aje/kwq049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915490PMC
June 2010