Weight change and risk of hyperglycaemia in elderly women.

BACKGROUND: Hyperglycaemia increases the risk of type 2 diabetes, heart disease and stroke, and is influenced by weight. However, the impact of preceding weight change on blood glycemia levels in late-life is less well understood. AIM: We studied the interplay between weight change and risk of hyperglycaemia in a prospective cohort of elderly women. METHODS: Elderly Caucasian women (age: 67.1 years at baseline, n = 1173) enrolled in the Prospective Epidemiological Risk Factor study with baseline and 13-year follow-up measurements of BMI and fasting glucose levels (FPG) and no previous history of diabetes or impaired fasting glucose. Multivariate logistic regression was used to determine risk of hyperglycaemia (FPG ≥ 5.6 mmol/L or HbA1c ≥ 42 mmol/mol) in normalweight (BMI ≤ 25 kg/m2), overweight (BMI = 25-29.9 kg/m2) and obese (BMI ≥ 30 kg/m2) women who either lost weight, were weight-stable or had gained weight at follow-up. RESULTS: Overweight and obese elderly women who had gained weight at follow-up presented an increased risk of hyperglycaemia, OR = 2.7 (1.6-4.6) and OR = 3.2 (1.5-6.8), compared to weight-stable normalweight women. Overweight and obese women who lost weight decreased their risk of hyperglycaemia to a level comparable to weight-stable normalweight women. Overweight and obese women with stable weight presented a two-fold increased risk of hyperglycaemia compared to normalweight weight-stable women. CONCLUSIONS: Losing weight in late life had a positive effect on the risk of hyperglycaemia in overweight and obese women, while further, weight gain increased the risk of hyperglycaemia. The study highlights that strategies to reduce weight in obese and overweight elderly women could have a positive influence on disease burden in late-life.

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

BACKGROUND: Truncated 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. OBJECTIVE: The 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. METHODS: Using 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. RESULTS: High 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. CONCLUSIONS: Measurement 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.

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.

Modifiable risk factors promoting neurodegeneration is associated with two novel brain degradation markers measured in serum.

There has been limited success with blood-based biomarkers of neurodegeneration. One perceived reason is that blood has no direct contact to the brain. Recently developed blood-based biomarkers of tau-degradation have shown promise as potential tools for peripheral assessment of neurodegeneration; however, factors contributing to the levels of these in blood are poorly understood. Using multiple linear regression analysis in cross-sectional data from an observational cohort (n = 5626), the aim was to examine which factors correlate to the serological levels of two novel biomarkers measuring truncated tau fragments (Tau-A and Tau-C) in serum. Platelets, albumin and several modifiable risk factors, including Body Mass Index, high density lipoprotein and white blood cell count were associated with the serum level of tau fragments. The factors associated with tau in serum may promote neurodegeneration and alter the permeability of the Blood Brain Barrier through chronic inflammation and vascular dysfunction. These data are of key importance for understanding the mechanism of release and subsequent peripheral processing of tau from the brain and will assist in the development of future blood-based biomarkers.

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.

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.

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 ±â€Š6.5) 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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: C1M, C4M, and VICM are elevated prior to cancer diagnosis. C1M and VICM are both independent predictors of increased cancer risk. IMPACT: C1M and VICM are predictors for increased risk of cancer. Cancer Epidemiol Biomarkers Prev; 25(9); 1348-55. ©2016 AACR.