Prospective Epidemiologic Risk Factor Research Articles

A Genetic Validation of the Neurodegeneration Biomarkers Tau-A and Tau-C - A Mendelian Randomization Study.

Disease modifying treatments for dementia are only just surfacing, and their development is still significantly hindered by the lack of validated tools for identification of subjects with subclinical disease. Much interest has been taken in developing accessible non-invasive serum biomarkers of neurodegeneration. Recent studies have identified caspase-3-cleaved tau (Tau-C), and ADAM-10 cleaved tau (Tau-A) as possible markers of preclinical neurodegenerative disease. To explore if serum levels of Tau-A and Tau-C change as a consequence of neurodegeneration. Cohort study with measurement of biomarkers and genome sequencing at baseline with follow-up after an average of 14 years. Postmenopausal Danish women from the Prospective Epidemiological Risk Factor (PERF) cohort (n=4968) Methods: Genotyping data was used to perform a Mendelian randomization analysis of serum levels of Tau-A and Tau-C in relation to a diagnosis of dementia at follow-up. A dementia diagnosis was defined as a composite of an all-cause dementia diagnosis derived from the Danish National Health registries, a self-reported diagnosis of dementia and/or cognitive test scores suggestive of dementia. Serum levels of Tau-A and Tau-C were measured blinded in samples from baseline in a CAP certified lab. The association with dementia was assessed using bi-directional one- and two- sample Mendelian randomization. A lead single nucleotide polymorphism (SNP) was identified for Tau-A (rs10414043) and Tau-C (rs429358), respectively were identified. Both were located in the APOE/C1 cluster on chromosome 19. APOE and EPOC1 variants were associated with lower levels of Tau-A and Tau-C levels - effect size -0.13, 95%CI [-0.17 - -0.09] log2 (ng/mL), p=7.05e-11 for rs10414043 association with Tau-A and effect size -0.12, 95%CI [-0.15 - -0.08] log2 (ng/mL), p=2e-11 for rs429358 association with Tau-C. When incorporating genetic data from a larger genetic study we found that Alzheimer's disease was marginally associated with a decreased Tau-A and Tau-C levels (Odds Ratio 0.97, 95%CI [0.93 - 1.00]. No association was found in the forward Mendelian randomization analysis. By combining genotype data with serum measurements of the novel biomarkers Tau-A and Tau-C, we conclude that Tau-A and Tau-C levels change because of neurodegeneration. We also conclude that lower serum-values of the biomarkers are associated with the presence of genetic variants commonly found in individuals suffering from late-onset Alzheimer's Dementia. These findings add to the growing data pointing towards Tau-A and Tau-C as valuable biomarkers for neurodegeneration.

A serological biomarker of type I collagen degradation is related to a more severe, high neutrophilic, obese asthma subtype

BackgroundAsthma is a heterogeneous disease; therefore, biomarkers that can assist in the identification of subtypes and direct therapy are highly desirable. Asthma is a chronic inflammatory disease that leads to changes in the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) degradation causing fragments of type I collagen that is released into circulation.ObjectiveHere, we asked if MMP-generated type I collagen (C1M) was associated with subtypes of asthma.MethodsC1M was serologically assessed at baseline in the adult participants of the All Age Asthma study (ALLIANCE) (n = 233), and in The Prospective Epidemiological Risk Factor study (PERF) (n = 283). In addition, C1M was assessed in mice sensitized to ovalbumin (OVA) and challenged with OVA aerosol. C1M was evaluated in mice with and without acute neutrophilic inflammation provoked by poly(cytidylic-inosinic) acid and mice treated with CP17, a peptide inhibiting neutrophil accumulation.ResultsSerum C1M was significantly increased in asthmatics compared to healthy controls (p = 0.0005). We found the increased C1M levels in asthmatics were related to blood neutrophil and body mass index (BMI) in the ALLIANCE cohort, which was validated in the PERF cohort. When patients were stratified into obese (BMI > 30) asthmatics with high neutrophil levels and uncontrolled asthma, this group had a significant increase in C1M compared to normal-weight (BMI < 25) asthmatics with low neutrophil levels and controlled asthma (p = 0.0277). C1M was significantly elevated in OVA mice with acute neutrophilic inflammation compared to controls (P = 0.0002) and decreased in mice treated with an inhibitor of neutrophil infiltration (p = 0.047).Conclusion & clinical relevanceC1M holds the potential to identify a subtype of asthma that relates to severity, obesity, and high neutrophils. These data suggest that C1M is linked to a subtype of overall inflammation, not only derived from the lung. The link between C1M and neutrophils were further validated in in vivo model.Trial registration(ALLIANCE, NCT02419274).

Endotrophin is associated with chronic multimorbidity and all-cause mortality in a cohort of elderly women.

BackgroundThe signalling peptide endotrophin is derived through proteolytic cleavage of the carboxyl-terminal during formation of type VI collagen. It is expressed by most descendants of the mesenchymal stem cells lineage, including adipocytes and fibroblasts, and have been proposed to be a central extracellular matrix hormone associated with several age-related diseases. We aimed to assess the association of endotrophin with chronic disease incidence and death in older women.Methods5,602 elderly Danish women from the observational, prospective cohort: The Prospective Epidemiological Risk Factor (PERF) study were included in the analysis which covered baseline (BL) and follow-up (FU) 14 years later. An elastic net was used to investigate the relative importance of 58 variables to serum endotrophin-levels. 20 chronic diseases were defined on the basis of clinical variables available along with diagnoses extracted from both the National Patient Register, the National Diabetes Register and the Danish Cancer Registry. The cross-sectional associations between endotrophin-levels and these 17 chronic age-related diseases were investigated using logistic regression and a set-analysis explored disease-combinations within multimorbidity. The association of endotrophin with mortality was assessed by Cox proportional hazard models.FindingsFormation of type III collagen (PRO-C3), age and creatine-levels were the most influential variables of endotrophin-levels. Several chronic diseases were significantly associated with endotrophin-levels independent of age and BMI including chronic kidney disease (BL OR=3.7, p < 0.001; FU OR = 7.9 p < 0.001), diabetes (BL OR = 1.5, p = 0.0015, FU OR=1.6, p = 0.004) and peripheral arterial disease (BL OR = 1.3, p = 0.029; FU OR=2.4, p < 0.001). Lastly, endotrophin-levels were significantly rising with number of morbidities (p < 0.001) and a predictor of death after adjusting for age and BMI (BL HR=1.95; FU HR = 2.00).InterpretationEndotrophin was associated with death and increased with number of morbidities. Endotrophin may be a central hormone of fibroblast that warrant investigation and possible targeted intervention in several chronic diseases.

1438-P: The Novel Extracellular Matrix Hormone Endotrophin, a Fragment of Collagen Type VI, Is Associated with Diabetes and Is a Risk Factor for Mortality in Elderly Women

As a result of the aging population and obesity, diabetes is a major, increasing public health issue approaching global epidemic proportions. It is well known that patients with diabetes have higher levels of inflammation and that the underlying pathology contributes to blood vessel damage resulting in cardiovascular complications. Recently it was suggested that a fragment of collagen type VI (COL VI), released during deposition, is in fact a novel hormone (endotrophin; ETP), suggesting the extracellular matrix (ECM) to be involved in the regulation of type 2 diabetes. In this study, we investigated the association of ETP (measured by the PRO-C6 ELISA) with diabetes and mortality in a large prospective cohort. From 1999-2001, 5855 postmenopausal women with a mean±SD age of 71±6.5 were included in the Prospective Epidemiological Risk Factor study, and visits were planned according to a pre-defined protocol. The diagnoses for diabetes and mortality were extracted from the Danish Health Registries. We measured ETP in serum of 5608 women at baseline (samples collected from 1999-2001). ETP levels were measured in 2016. ETP levels were significantly elevated in women who died (p&amp;lt;0.0001). Additionally, we found that ETP levels were higher in women diagnosed with diabetes prior to baseline visit (n=206) compared to women diagnosed with diabetes after baseline (n=515, p=0.017), that ETP were higher in women with diabetes prior to baseline compared to healthy women (p&amp;lt;0.0001), and a trend of higher levels of ETP in women diagnosed with diabetes after baseline compared to healthy women (p=0.10). In conclusion, we demonstrate that the hormone ETP, a biomarker also reflecting COL VI deposition, was increased in serum of postmenopausal women with diabetes compared to healthy women. In addition, we show that ETP was associated with mortality, suggesting that turnover of the ECM is very important in metabolic disorders. Disclosure A. Møller: None. D.G.K. Rasmussen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Stock/Shareholder; Self; Nordic Bioscience. C. Christiansen: None. L.M. Staunstrup: None. C.L. Bager: None. Funding Danish Research Foundation

Atrial fibrillation is associated with lean body mass in postmenopausal women

This study investigated the association between body composition and risk of atrial fibrillation (AF) in postmenopausal women. In a retrospective analysis we assessed data from 5704 postmenopausal women (age 70.7 ± 6.5 yrs.) who in 1999–2001 participated in The Prospective Epidemiological Risk Factor study with body composition assessed by dual-energy X-ray absorptiometry. Outcomes were obtained from Danish Health Registries and body composition association to risk of AF was evaluated by univariable and multivariable Cox Hazard regression. 850 women developed AF after baseline. High lean body mass was associated with increased risk of AF in multivariable analyses, adjusting for body mass index (BMI), height or weight (adjusted for: BMI, hazard ratio (HR) 1.49, 95% Confidence Interval (1.22–1.80); height, HR 1.27 (1.03–1.56); weight, 1.33 (1.06–1.65)). Height and weight were associated with increased risk of AF in multivariable analyses adjusting for body composition measures. When adjusting for total lean mass, only height remained statistically significant (HR 1.34 (1.09–1.64)). In a cohort of elderly Caucasian women, high lean body mass, height and weight were associated with increased risk of AF and the variables remained significant after adjusting for age and other known risk factors of AF.

Incidence of total hip and total knee replacements from the prospective epidemiologic risk factor study: considerations for event driven clinical trial design

BackgroundOsteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an endpoint in event-driven clinical trials within a reasonable duration. We explored the incidence of TJR in the Prospective Epidemiologic Risk Factor (PERF I) study.MethodsA total of 5855 Danish postmenopausal women aged 49–88 enrolled in the PERF I study during 1999–2001 (baseline). Three-, six- and twelve-year follow-up data from the Danish National Patient Registry was collected, including occurrence of TJR and OA diagnosis. At baseline the women were asked whether they had OA.ResultsThe women with a TJR diagnosis before or after baseline were on average 1 year older (p < 0.001) and heavier (p < 0.001), compared to women with no TJR. The 3-, 6- and 12-year cumulative incidences were 1.1, 2.4 and 6.0% for TKR, and 2.1, 4.4 and 9.3% for THR. For those with an OA diagnosis at baseline the respective incidences were 2.7, 5.6 and 11.7% and 3.9, 7.2 and 13.6%ConclusionsWithin 3, 6 or 12 years TJR incidences were double for women with an OA diagnosis compared to the all-comer population. TJRs are frequent amongst elderly women with OA and it is, therefore, feasible to conduct event-driven clinical trials where TJR is the endpoint demonstrating clinical benefit of a novel disease-modifying OA drug (DMOAD).

Low bone turnover levels predict increased risk of cancer.

Several epidemiological studies have shown an association between bone mineral density (BMD) and risk of breast cancer in postmenopausal women, but it remains unknown whether bone turnover is associated with increased risk of cancer. The aim of this study was to investigate if markers of bone formation and resorption are associated with increased risk of cancer. The study population included 5855 postmenopausal Danish women enrolled in the Prospective Epidemiologic Risk Factor (PERF) study. Cancer diagnosis was obtained from the Danish Cancer Registry. Baseline spine, femur, and whole-body BMD were evaluated by DXA-scanners. Baseline bone turnover (CTX-1 and osteocalcin) were measured in serum. Multivariate Cox analysis was performed with 3, 6 and 12 years of follow-up. All continuous variables were transformed into z-score for the cox analyses. 252 developed cancer after 3 years, 462 developed cancer after 6 years, and 881 developed cancer with 12 years of follow-up. CTX-1, osteocalcin and spine BMD were all predictors of cancer at all time points (3 years of follow-up: Spine BMD, HR = 1.20, p = 0.003; CTX-1, HR = 0.82, p = 0.005; osteocalcin, HR = 0.75, p < 0.001). After adjusting for cancer risk factors and other bone measures CTX-1 and osteocalcin remained independent predictors of cancer (3 years of follow-up: CTX-1, HR = 0.82, p = 0.02; osteocalcin, HR = 0.75, p = 0.002). We found that levels of the bone turnover markers CTX-1 and osteocalcin were inversely associated with risk of cancer independent of BMD and other known cancer risk factors in postmenopausal women.

Cancer risk in relation to body fat distribution, evaluated by DXA-scans, in postmenopausal women \u2013 the Prospective Epidemiological Risk Factor (PERF) study

Studies with direct measures of body fat distribution are required to explore the association between central and general obesity to cancer risk in postmenopausal women. This study investigates the association between central obesity and general obesity to overall/site-specific cancer risk in postmenopausal women. The analysis included 4,679 Danish postmenopausal women. Body fat distribution was evaluated by whole-body dual-energy X-ray absorptiometry scanners. Cancer diagnoses were extracted from the Danish Cancer Registry and multivariable Cox regression models explored the association between cancer risk and central obesity after adjusting for BMI. Our results showed that high central obese women had a 50% increased risk of overall cancer relative to low central obese women (Q1vs.Q4: [HR:1.50, CI:1.20–1.88]). For site-specific cancers, central obesity was significantly associated with Respiratory (Q1vs.Q4: [HR:2.01, CI:1.17–3.47]), Gastrointestinal (Q1vs.Q4: [HR:1.55, CI:0.99–2.41]) and Female genital organs (Q1vs.Q4: [HR:1.95, CI:1.00–3.78]) cancer diagnoses. Sub-analyses stratified by smoking-habits found a significant association between central obesity and a cancer diagnosis for current (Q1vs.Q4: [HR:1.93, CI:1.25–2.99]) and former smokers (Q1vs.Q4: [HR:1.90, CI:1.23–2.94]). These analyses suggest that central obesity is associated with some cancers in postmenopausal women independent of BMI.

Incidence of Total Joint Replacements from the Prospective Epidemiologic Risk Factor Study: Considerations for Event Driven Clinical Trial Design

Background: Osteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an endpoint in event-driven clinical trials within a reasonable duration. We explored the incidence of TJR in the Prospective Epidemiologic Risk Factor (PERF I) study. Methods: A total of 5,855 Danish postmenopausal women aged 49-88 enrolled in the PERF I study during 1999-2001 (baseline). Three-, six- and twelve-year follow-up data from the Danish National Patient Registry was collected, including occurrence of TJR and OA diagnosis. At baseline the women were asked whether they had OA. Findings: The TJR women were on average 1 year older (p<0.001) and heavier (p<0.001), compared to women with no TJR in the follow-up period. The 3-, 6- and 12-year cumulative incidences were 1.1, 2.4 and 6.0% for TKR, and 2.1, 4.4 and 9.3% for THR. For those with an OA diagnosis at baseline the respective incidences were 2.7, 5.6 and 11.7% and 3.9, 7.2 and 13.6%. Interpretation: Within 3, 6 or 12 years TJR incidences were double for women with an OA diagnosis compared to the all-comer population. TJRs are frequent amongst elderly women with OA and it is, therefore, feasible to conduct event-driven clinical trials where TJR is the endpoint demonstrating clinical benefit of a novel disease-modifying OA drug (DMOAD). Funding Statement: The Danish Research Foundation funded the PERF I study. Declaration of Interests: Bager is employed at ProScion. Karsdal, Bihlet, Thudium, Byrjalsen and Bay-Jensen are employed at Nordic Bioscience. Karsdal, Bihlet, and Bay-Jensen holds stocks in Nordic Bioscience. Ethics Approval Statement: The PERF I study was carried out in accordance with applicable regulatory and ethical guidelines, and the study protocol was approved by the local ethics committees. All participants signed an informed consent.

Bone and Soft Tissue Turnover in Relation to All-cause Mortality in Postmenopausal Women.

The relationship between levels of extracellular matrix (ECM) turnover and mortality is currently unknown. The study aimed to determine if levels of ECM turnover are predictors of all-cause mortality in a large cohort of postmenopausal women. 5,855 postmenopausal Danish women enrolled in the Prospective Epidemiologic Risk Factor (PERF) study. Baseline demographics and serum were collected at registration. Dates of death were obtained from the Danish Death Registry. ECM turnover was evaluated by serological biomarkers measuring bone (telopeptide of type I collagen [CTX-1] and osteocalcin) and soft tissue (formation of type VI collagen [PRO-C6], MMP-degraded type IV collagen [C4M], formation of type III collagen [PRO-C3], and MMP-degraded type I collagen [C1M]) turnover. Multivariate Cox analyses were performed with 3, 5, and 15 years of follow-up. The association of bone turnover (CTX-1 and osteocalcin) with all-cause mortality was U-shaped for all time periods. After adjustment for possible confounders, the lowest quintile of bone formation and degradation remained significant for all time periods. We observed J-shaped association between all-cause mortality and PRO-C6, C4M, and PRO-C3, and there was a linear association between C1M and all-cause mortality. After adjustment for possible confounders, the highest quintile of the soft tissue turnover biomarkers (PRO-C6, C4M, PRO-C3, and C1M) remained significantly associated with all-cause mortality for all time periods. Both low and high levels of tissue turnover were associated with increased risk of all-cause mortality in postmenopausal women. Overall, these results highlight the importance of bone and soft tissue homeostasis.

Two novel blood-based biomarker candidates measuring degradation of tau are associated with dementia: A prospective study

BackgroundTruncated tau appears to be specifically related to disease pathology and recent studies have shown the presence and elevation of several truncated tau species in Cerebrospinal fluid (CSF) of subjects with Alzheimer’s disease (AD); however, the relevance of truncated Tau measurements in blood is still being studied.ObjectiveThe aim of the current study was to assess the longitudinal associations between baseline levels of two novel blood biomarker candidates measuring truncated tau, Tau-A and Tau-C, and the risk of incident dementia and AD in elderly women.MethodsUsing solid phase competitive ELISA, two tau fragments were detected in serum of 5,309 women from the Prospective Epidemiological Risk Factor study. The study was an observational, prospective study of Danish postmenopausal women. Subjects were followed with registry-linkage for up to 15 years (median follow-up time 13.7 years). Cox regression was used to assess the utility of the biomarker candidates in relation to dementia and AD.ResultsHigh levels of Tau-A and Tau-C (above the median) in blood were associated with lower risk of dementia and AD (Tau-A: Dementia HR[95% CI] = 0.85[0.70–1.04]; AD 0.71[0.52–0.98] and Tau-C: Dementia 0.84[0.70–1.00]; AD 0.78[0.60–1.03]). Tau-C gave a very modest increase in the AUC in a 5-year prediction horizon as compared to a reference model with age and education, while a combination of the two did not improve their predictive capacity.ConclusionsMeasurement of tau in serum is feasible. The serological tau turnover profile may be related to the diagnosis and development of dementia and AD. The exact processing and profile in serum in relation to cognitive disorders remains to be further assessed to provide simple non-invasive tests to identify subjects with progressive cognitive disorders.

Total joint replacement (TJR) as clinical endpoint in OA; prevalence and incidence rates of TJRS from the Prospective Epidemiologic Risk Factor (PERF I) study

Total joint replacement (TJR) as clinical endpoint in OA; prevalence and incidence rates of TJRS from the Prospective Epidemiologic Risk Factor (PERF I) study

Matrix Metalloproteinase Mediated Type I Collagen Degradation is an Independent Predictor of Increased Risk of Acute Myocardial Infarction in Postmenopausal Women

Acute myocardial infarction (AMI) is often underdiagnosed in women. It is therefore of interest to identify biomarkers that indicate increased risk of AMI and thereby help clinicians to have additional focus on the difficult AMI diagnosis. Type I Collagen, a component of the cardiac extracellular matrix, is cleaved by matrix metalloproteinases (MMPs) generating the neo-epitope C1M. We investigated the association between serum-C1M and AMI and evaluated whether C1M is a prognostic marker for outcome following AMI. This study is based on The Prospective Epidemiological Risk Factor (PERF) Study including postmenopausal women. 316 out of 5,450 women developed AMI within the follow-up period (14 years, median). A multivariate Cox analysis assessed association between serum-C1M and AMI, and re-infaction or death subsequent to AMI. The risk of AMI increased by 18% (p = 0.03) when serum-C1M was doubled and women in the highest quartile had a 33% increased risk compared to those in the low quartiles (p = 0.025). Serum-C1M was, however not related to reinfarction or death subsequent to AMI. In this study C1M was be an independent risk factor for AMI. Measuring MMP degraded type I collagen could be useful for prediction of increased risk of AMI if replicated in other cohorts.

Metabolic Syndrome, Insulin Resistance, and Cognitive Dysfunction: Does Your Metabolic Profile Affect Your Brain?

Dementia and type 2 diabetes are both characterized by long prodromal phases, challenging the study of potential risk factors and their temporal relation. The progressive relation among metabolic syndrome, insulin resistance (IR), and dementia has recently been questioned, wherefore the aim of this study was to assess the potential association among these precursors of type 2 diabetes and cognitive dysfunction. Using data from the Prospective Epidemiological Risk Factor (PERF) Study (n = 2,103), a prospective study of elderly women in Denmark, we found that impaired fasting plasma glucose concentration was associated with 44% (9-91%) larger probability of cognitive dysfunction. In addition, subjects above the HOMA-IR threshold (HOMA-IR >2.6) had 47% (9-99%) larger odds of cognitive dysfunction. The associations could indicate that a significant proportion of dementia cases in women is likely to be preventable by effective prevention and control of the insulin homeostasis.

Excessive matrix metalloprotease-mediated degradation of interstitial tissue (type I collagen) independently predicts short-term survival in an observational study of postmenopausal women diagnosed with cancer.

Extensive tissue remodeling mediated by matrix metalloproteases (MMPs) is an important part of cancer. The aim of this study was to investigate whether serum biomarkers reflecting MMP-mediated degradation of type I collagen (C1M), type IV collagen (C4M) and citrullinated vimentin (VICM) were predictive of cancer-specific mortality. Between 1999 and 2001, 5855 Danish postmenopausal women participated in The Prospective Epidemiologic Risk Factor (PERF I) study. Demographics and serum samples were collected at enrolment. Cancer diagnosis, and cause and time of death were obtained from Danish registries. C1M, C4M and VICM were measured by ELISA. Hazard ratios (HR) and Kaplan-Meier curves were applied to assess mortality at 3 and 12 years of follow-up for women diagnosed with cancer within 3 years from blood sampling. Within 3 years from blood sampling, 250 women had been diagnosed with cancer. C1M and VICM were associated with survival over time at 3 years of follow-up. Only C1M was predictive of mortality at 3 years follow-up: the adjusted HR was 2.65 [95% CI: 1.08-6.51]. In conclusion, C1M and VICM are associated with survival in postmenopausal women with cancer, and C1M is an independent risk factor for cancer-specific mortality. Thus, quantification of tissue remodeling is important in cancer.

Objective Cognitive Impairment and Progression to Dementia in Women: The Prospective Epidemiological Risk Factor Study.

Identification of subjects with a progressive disease phenotype is an urgent need in the pharmaceutical industry where most of the recent clinical trials in Alzheimer's disease have failed. The objective of this study was to identify subgroups of individuals with objective cognitive impairment (OCI), who were most likely to progress to dementia and to identify the risk factors associated with progression. Prospective cohort study. Population-based. 5,380 elderly women from Denmark. The Short Blessed Test and a category fluency test with animal naming, was used to assess cognitive function, and to classify them into different groups of OCI. OCI was identified in 852 subjects at baseline. The risk of dementia was elevated for OCI subjects as compared to subjects with normal cognition (HR 1.46[1.19-1.79]). The courses of OCI were studied in a sub-cohort who completed the cognitive assessment at both the baseline and the follow-up visit (n = 1,933). Of these subjects 203 had OCI at baseline. The multi-domain subtypes of OCI were associated with progressive OCI. Subjects most likely to progress were older, physically inactive, had a higher level of total cholesterol (>6.5 mmol/L) and had a history of depression as compared to subjects with a non-progressive course of OCI. In this cohort we identified a risk profile associated with progression from OCI in older women. The degree of impairment at baseline was an important predictor of conversion to dementia, additionally several modifiable risk factors were associated with progression.

Metabolic syndrome and subsequent risk of type 2 diabetes and cardiovascular disease in elderly women: Challenging the current definition.

The prognostic value of the metabolic syndrome (MetS) is believed to vary with age. With an elderly population expecting to triple by 2060, it is important to evaluate the validity of MetS in this age group. We examined the association of MetS risk factors with later risk of type 2 diabetes (T2DM) and cardiovascular disease (CVD) in elderly Caucasian women. We further investigated if stratification of individuals not defined with MetS would add predictive power in defining future disease prevalence of individuals with MetS.The Prospective Epidemiological Risk Factor Study, a community-based cohort study, followed 3905 Danish women since 2000 (age: 70.1 ± 6.5) with no previous diagnosis of T2DM or CVD, holding all measurements used for MetS definition; central obesity, hypertension, hyperlipidemia, and hyperglycemia combined with register-based follow-up information.Elderly women with defined MetS presented a 6.3-fold increased risk of T2DM (95% confidence interval: [3.74-10.50]) and 1.7-fold increased risk of CVD (1.44-2.05) compared to women with no MetS risk factors. Subdividing the control group without defined MetS revealed that both centrally obese controls and controls holding other MetS risk factors also had increased risk of T2DM (hazard ratio (HR) = 2.21 [1.25-3.93] and HR = 1.75 [1.04-2.96]) and CVD (HR = 1.51 [1.25-1.83] and HR = 1.36 [1.15-1.60]) when compared to controls with no MetS risk factors.MetS in elderly Caucasian women increased risk of future T2DM and CVD. While not defined with MetS, women holding only some risk factors for MetS were also at increased risk of T2DM or CVD compared to women with no MetS risk factors.

Remodeling of the Tumor Microenvironment Predicts Increased Risk of Cancer in Postmenopausal Women: The Prospective Epidemiologic Risk Factor (PERF I) Study.

An altered tumor microenvironment is one of the earliest signs of cancer and an important driver of the disease. We have seen previously that biomarkers reflecting tumor microenvironment modifications, such as matrix metalloproteinase (MMP)-degraded type 1 collagen (C1M), MMP-degraded type IV collagen (C4M), and citrullinated and MMP-degraded vimentin (VICM), were higher in the serum of cancer patients than in healthy controls. However, it is not known if these biomarkers could predict an increased risk of cancer. The aim of this study was to investigate whether C1M, C4M, and VICM were elevated prior to diagnosis of solid cancers in a large prospective study. Between 1999 and 2001, 5,855 postmenopausal Danish women ages 48 to 89 years enrolled in the Prospective Epidemiologic Risk Factor study. Baseline demographics and serum were collected at the time of registration. Follow up cancer diagnoses were obtained from the Danish Cancer Registry in 2014. Serum C1M, C4M, and VICM levels were measured by competitive ELISAs. A total of 881 women were diagnosed with solid cancers after baseline. C1M, C4M, and VICM levels were significantly elevated in women diagnosed less than 1 year after baseline. C1M and VICM, but not C4M, were independent predictors of increased risk of cancer. C1M, C4M, and VICM are elevated prior to cancer diagnosis. C1M and VICM are both independent predictors of increased cancer risk. C1M and VICM are predictors for increased risk of cancer. Cancer Epidemiol Biomarkers Prev; 25(9); 1348-55. ©2016 AACR.

TAU-C, A CASPASE-3 CLEAVED FRAGMENT OF TAU: A SERUM BIOMARKER FOR PRECLINICAL DEMENTIA

There is a clear need for non-invasive and reliable biomarkers to aid in early prognosis, diagnosis and early efficacy assessment for dementia disorders. The caspase-3-generated fragment of tau (Tau-C), incorporating the Asp421 site, is considered a key player in the filament formation eventually leading to tangle formation (Rissman et al. 2004). The aim of this study was to investigate this particular pathological protein fragment in serum, in a large prospective cohort of elderly women who has been followed for up to 15 years. Using competitive ELISA, Tau-C was measured in baseline serum samples from subjects in the Prospective Epidemiological Risk Factor (PERF) Study (n=5,632). The subjects were stratified in three groups; dementia free controls (n=5,005), subjects with established dementia (n=15), and subjects later diagnosed with dementia (n=612). The levels of Tau-C were compared using Kruskal-Wallis test. The prognostic utility in combination with baseline cognitive performance, was assessed in relation to risk of dementia using Cox regression. Tau-C levels were dichotomized using the median. The cognitive test was the Short Blessed Test. Our data suggest that Tau-C could have prognostic utility as an early marker for dementia. The increased risk of dementia for subjects with low levels of Tau-C and normal cognition could reflect the accumulation of caspase-cleaved Tau in neuronal cells in an early disease stage. Opposite, the possible increased risk for subjects with high Tau-C levels and severe impairment could indicate that these subjects are actually in a diseased stage, where dying neurons release caspase-cleaved tau into the surroundings.

Late-Life Risk Factors for All-Cause Dementia and Differential Dementia Diagnoses in Women: A Prospective Cohort Study.

Since the first evidence of a decline in dementia incidence was reported in 2011, the focus on modifiable risk factors has increased. The possibility of risk factor intervention as a prevention strategy has been widely discussed; however, further evidence in relation to risk factors is still needed. The Prospective Epidemiologic Risk Factor (PERF I) study was an observational prospective study of postmenopausal Danish women who were initially examined between 1999 and 2001 (n = 5855). Follow-up data on diagnosis and survival as of December 31, 2014 was retrieved from the National Danish Patient Registry and the National Danish Causes of Death Registry. Cox proportional hazards regression model was applied to calculate adjusted hazard ratios (HR) for selected risk factors for dementia. Of 5512 eligible subjects, 592 developed dementia within the follow-up period of maximum 15 years. The independent factors associated with increased risk of all-cause dementia were depression (HR = 1.75 [95% CI 1.32-2.34]) and impaired fasting glucose levels. A dose-response relationship was observed between fasting glucose level and risk of dementia with HRs of 1.25 [1.05-1.49] and 1.45 [1.03-2.06] for impaired (5.6-6.9 mmol/L) and hyperglycemic (≥7.0 mmol/L) glucose levels, respectively. The factors associated with a decreased risk of dementia were overweight in late-life (HR = 0.75 [0. 62-0.89]) and physical activity at least once weekly (HR = 0.77 [0.61-0.96]). The identified risk factors for dementia in women in late-life are all considered modifiable. This supports the notion that prevention strategies may improve the poor future prospects for dementias in the ageing population.