Skin autofluorescence, reflecting accumulation of advanced glycation end products, and the risk of dementia in a population-based cohort.

Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia. Of these, 1504 also underwent brain MRI, on which measures of brain atrophy and cerebral small vessel disease were assessed. All participants were followed for the incidence of dementia until 2020. Of 2922 participants (mean age 72.6 years, 57% women), 123 developed dementia. Higher skin autofluorescence (per standard deviation) was associated with an increased risk of dementia (hazard ratio 1.21 [95% confidence interval 1.01-1.46]) and Alzheimer's disease (1.19 [0.97-1.47]), independently of age and other studied potential confounders. Stronger effects were seen in apolipoprotein E (APOE) ε4 carriers (1.34 [0.98-1.82]) and in participants with diabetes (1.35 [0.94-1.94]). Participants with higher skin autofluorescence levels also had smaller total brain volumes and smaller hippocampus volumes on MRI, and they had more often lacunes. These results suggest that AGEs may be involved in dementia pathophysiology.

Advanced glycation end products measured by skin autofluorescence and subclinical cardiovascular disease: the Rotterdam Study.

BACKGROUND: Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD. METHODS: In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF). Prevalent MI was obtained from digital medical records. Carotid plaques, carotid intima-media thickness (IMT), coronary artery calcification (CAC), pulse wave velocity (PWV), and hypertension were assessed. Associations of SAF with endophenotypes were investigated in logistic and linear regression models adjusting for common cardiovascular risk factors. Effect modification by sex, diabetes mellitus, and chronic kidney disease (CKD) was tested. RESULTS: 3001 participants were included (mean age 73 (SD 9) years, 57% women). One unit higher SAF was associated with the presence of carotid plaques (OR 1.2 (0.92, 1.57)), a higher max IMT (0.08 SD (0.01, 0.15)), higher CAC (OR 2.2 (1.39, 3.48)), and PWV (0.09 SD (0.01, 0.16)), but not with hypertension (OR 0.99 (0.81, 1.21)). The associations with endophenotypes were more pronounced in men and participants with diabetes or CKD with significant interactions. CONCLUSIONS: Previously documented associations between SAF and CVD, also found in our study, may be explained by the endophenotypes atherosclerosis and arterial stiffness, especially in men and individuals with diabetes or CKD, but not by hypertension. Longitudinal studies are needed to replicate these findings and to test if SAF is an independent risk factor or biomarker of CVD. TRIAL REGISTRATION: The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl ) and the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/ ) under shared catalogue number NTR6831.

Dietary advanced glycation end-products (dAGEs) intake and its relation to sarcopenia and frailty - The Rotterdam Study.

Studies on mice have shown a relationship between dietary intake of advanced glycation end-products (dAGEs) and deterioration of musculoskeletal health, but human studies are absent. We investigated the relationship between dietary intake of carboxymethyllysine (dCML) - an AGE prototype - and risk of sarcopenia at baseline and after 5 years of follow-up and a single evaluation of physical frailty in participants from the population-based Rotterdam Study. Appendicular lean mass (ALM) was obtained using insight dual-energy X-ray absorptiometry and hand grip strength (HGS) using a hydraulic hand dynamometer. Subjects with both low ALM and weak HGS were classified as having sarcopenia. Frailty (yes/no) was defined by presence of ≥3 and pre-frailty by presence of 1 or 2 components namely, exhaustion, weakness, slowness, weight loss or low physical activity. dCML was calculated using a food frequency questionnaire and dAGE databases. Logistic regression analysis was used to evaluate the odds of physical frailty and prevalent sarcopenia at baseline and follow-up and incident sarcopenia. 2782 participants with an age 66.4 ± 9.9 years and dCML intake 3.3 ± 1.3 mg/day, had data on sarcopenia at both time points. Of whom 84 had sarcopenia at baseline and 73 developed sarcopenia at follow-up. We observed an association of one SD increase in dCML intake with prevalent sarcopenia at baseline [odds ratio, OR = 1.27 (1.01-1.59)] and no association of dCML with incident sarcopenia at 5-year follow-up [OR = 1.12 (0.86-1.44)]. For frailty we analyzed 3577 participants, of whom 1972 were pre-frail and 158 were frail. We observed no association of dCML with either pre-frailty [OR = 0.99 (0.91-1.07)] or frailty [OR = 1.01 (0.83-1.22)] when non-frail subjects were used as reference. Our results show an association of dAGEs with sarcopenia cross-sectionally but not longitudinally where inconclusive findings are observed possibly due to a very low incidence of sarcopenia. There was no association with frailty cross-sectionally.

Methylglyoxal - an advanced glycation end products (AGEs) precursor - Inhibits differentiation of human MSC-derived osteoblasts in vitro independently of receptor for AGEs (RAGE).

A major precursor of advanced glycation end-products (AGEs) - methylglyoxal (MG) - is a reactive carbonyl metabolite that originates from glycolytic pathways. MG formation and accumulation has been implicated in the pathogenesis of diabetes and age-related chronic musculoskeletal disorders. Human bone marrow-derived stromal cells (BMSCs) are multipotent cells that have the potential to differentiate into cells of mesenchymal origin including osteoblasts, but the role of MG on their differentiation is unclear. We therefore evaluated the effect of MG on proliferation and differentiation of BMSC-derived osteoblasts. Cells were treated with different concentrations of MG (600, 800 and 1000 µM). Cell viability was assessed using a Cell Counting Kit-8 assay. Alkaline phosphatase (ALP) activity and calcium deposition assays were performed to evaluate osteoblast differentiation and mineralization. Gene expression was measured using qRT-PCR, whereas AGE specific receptor (RAGE) and collagen 1 were examined by immunocytochemistry and Western blotting. RAGE knockdown was performed by transducing RAGE specific short hairpin RNAs (shRNAs) using lentivirus. During osteogenic differentiation, MG treatment resulted in reduction of cell viability (27.7 %), ALP activity (45.5 %) and mineralization (82.3 %) compared to untreated cells. MG significantly decreased expression of genes involved in osteogenic differentiation - RUNX2 (2.8 fold), ALPL (3.2 fold), MG detoxification through glyoxalase - GLO1 (3 fold) and collagen metabolism - COL1A1 (4.9 fold), COL1A2 (6.8 fold), LOX (5.4 fold) and PLOD1 (1.7 fold). MG significantly reduced expression of collagen 1 (53.3 %) and RAGE (43.1 %) at protein levels. Co-treatment with a MG scavenger - aminoguanidine - prevented all negative effects of MG. RAGE-specific knockdown during MG treatment did not reverse the effects on cell viability, osteogenic differentiation or collagen metabolism. In conclusion, MG treatment can negatively influence the collagen metabolism and differentiation of BMSCs-derived osteoblasts through a RAGE independent mechanism.

Skin Autofluorescence, a Noninvasive Biomarker of Advanced Glycation End-products, Is Associated With Frailty: The Rotterdam Study.

BACKGROUND: Accumulation of advanced glycation end-products (AGEs) in tissues has been linked to various age-related disease phenotypes. Therefore, we investigated the potential relationship between skin AGE accumulation and frailty. METHODS: A cross-sectional analysis was performed on 2 521 participants from the Rotterdam Study. Skin AGEs were assessed as skin autofluorescence (SAF) using the AGE reader™. We used 2 approaches to define frailty. Fried's criteria, including weight loss, weakness, slow gait speed, exhaustion, and low physical activity, were used to define physical frailty (presence of ≥3 components) and prefrailty (presence of ≤2 components). Rockwood's concept, including 38 deficits from physical and psychosocial health domains, was used to calculate the frailty index (score 0-1). Multinomial logistic and multivariate linear regression were used with SAF as exposure and physical frailty (ordinal) and frailty index (continuous) as outcome adjusting for age, sex, diabetes, renal function, socioeconomic status, and smoking status. RESULTS: The mean SAF was 2.39 ± 0.49 arbitrary units and the median age was 74.2 (14.0) years. Regarding physical frailty, 96 persons (4%) were frail and 1 221 (48%) were prefrail. Skin autofluorescence was associated with both being prefrail (odds ratio [95% confidence interval] = 1.29 [1.07-1.56]) and frail (1.87 [1.20-2.90]) compared with nonfrail. Regarding the frailty index, the median value was 0.14 (0.10-0.19) and higher SAF was also associated with a higher frailty index (coefficient, B = 0.017 (0.011-0.023]). CONCLUSIONS: Higher skin AGEs are associated with both physical frailty and frailty index. Longitudinal studies are needed to evaluate the causality and the potential of SAF as a biomarker to screen frailty.

Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-products, Is Associated With Sarcopenia.

BACKGROUND: Accumulation of advanced glycation end-products (AGEs) in skeletal muscle has been implicated in development of sarcopenia. AIM: To obtain further insight in the pathophysiology of sarcopenia, we studied its relationship with skin AGEs in the general population. METHODS: In a cross-sectional analysis, 2744 participants of northern European background, mean age 74.1 years, were included from the Rotterdam Study. Skin AGEs were measured as skin autofluorescence (SAF) using AGE ReaderTM, appendicular skeletal mass index (ASMI) using insight dual-energy X-ray absorptiometry, hand grip strength (HGS) using a hydraulic hand dynamometer, and, in a subgroup, gait speed (GS) measured on an electronic walkway (n = 2080). We defined probable sarcopenia (low HGS) and confirmed sarcopenia (low HGS and low ASMI) based on the European Working Group on Sarcopenia in Older People (EWGSOP2) revised criteria cutoffs. Multivariate linear and logistic regression were performed adjusting for age, sex, body fat percentage, height, renal function, diabetes, and smoking status. RESULTS: The prevalence of low ASMI was 7.7%; probable sarcopenia, 24%, slow GS, 3%; and confirmed sarcopenia, 3.5%. SAF was inversely associated with ASMI [ß -0.062 (95% CI -0.092, -0.032)], HGS [ß -0.051 (95% CI -0.075, -0.026)], and GS [ß -0.074 (95% CI -0.116, -0.033)]. A 1-unit increase in SAF was associated with higher odds of probable sarcopenia [odds ratio (OR) 1.36 (95% CI 1.09, 1.68)] and confirmed sarcopenia [OR 2.01 (95% CI 1.33, 3.06)]. CONCLUSION: Higher skin AGEs are associated with higher sarcopenia prevalence. We call for future longitudinal studies to explore the role of SAF as a potential biomarker of sarcopenia.

Updated guidance on the management of cancer treatment-induced bone loss (CTIBL) in pre- and postmenopausal women with early-stage breast cancer.

INTRODUCTION: Adjuvant endocrine therapy induces bone loss and increases fracture risk in women with hormone-receptor positive, early-stage breast cancer (EBC). We aimed to update a previous position statement on the management of aromatase inhibitors (AIs) induced bone loss and now included premenopausal women. METHODS: We conducted a systematic literature search of the medical databases from January 2017 to May 2020 and assessed 144 new studies. RESULTS: Extended use of AIs beyond 5 years leads to persistent bone loss in breast cancer extended adjuvant trials and meta-analyses. In addition to bone mineral density (BMD), vertebral fracture assessment (VFA) and trabecular bone score (TBS) were shown to independently predict fracture risk in real life prospective studies. FRAX® tool does not seem to be reliable for assessing fracture risk in CTIBL. In premenopausal women, there is strong evidence that intravenous zoledronate prevents bone loss but weak conflicting evidence on reducing disease recurrence from independent randomised controlled trials (RCTs). In postmenopausal women, the strongest evidence for fracture prevention is for denosumab based on a well-powered RCT while there is strong evidence for bisphosphonates (BPs) to prevent and reduce CTIBL but no convincing data on fractures. Adjuvant denosumab has failed to show anticancer benefits in a large, well-designed RCT. DISCUSSION AND CONCLUSIONS: Extended use of AIs and persistent bone loss from recent data reinforce the need to evaluate fracture risk in EBC women initiated on AIs. Fracture risk should be assessed with clinical risk factors and BMD along with VFA, but FRAX is not adapted to CTIBL. Anti-resorptive therapy should be considered in those with a BMD T-score < -2.0 SD or with ≥ 2 clinical risk factors including a BMD T-score < -1.0 SD. In premenopausal women, intravenous zoledronate is the only drug reported to prevent bone loss and may have additional anticancer benefits. In postmenopausal women, either denosumab or BPs can be prescribed for fracture prevention with pertinent attention to the rebound phenomenon after stopping denosumab. Adjuvant BPs, in contrast to denosumab, have shown high level evidence for reducing breast cancer recurrence in high-risk post-MP women which should be taken into account when choosing between these two.

Assessment of Advanced Glycation End Products and Receptors and the Risk of Dementia.

Importance: Advanced glycation end products (AGEs) and their receptor (RAGE) are implicated in the pathophysiological processes of dementia and potentially underlie the association of diabetes with neurodegeneration. However, longitudinal studies examining this association are lacking. Objective: To determine whether markers of the AGE-RAGE system are associated with prevalent and incident dementia and with cognition. Design, Setting, and Participants: In this population-based cohort study including participants from the prospective Rotterdam Study, extracellular newly identified RAGE binding protein (EN-RAGE) and soluble RAGE (S-RAGE) were measured in plasma collected between 1997 and 1999 in a random selection of participants, and additionally in participants with prevalent dementia. Participants without dementia were followed up for dementia until 2016. Skin AGEs, measured as skin autofluorescence, and cognition were measured between 2013 and 2016 in participants without dementia. Data analysis was performed from June 2019 to December 2019. Exposures: EN-RAGE, S-RAGE, and skin autofluorescence. Main Outcomes and Measures: Prevalent and incident dementia and cognition, adjusted for potential confounders, including age, sex, diabetes, educational level, APOE ε4 carrier status, smoking, and estimated glomerular filtration rate. Results: Of 3889 included participants (mean [SD] age, 72.5 [8.9] years; 2187 [56.2%] women), 1021 participants had data on plasma markers (mean [SD] age 73.6 [7.8] years; 564 [55.2%] women), 73 participants had dementia at baseline, and during 10 711 person-years of follow-up, 161 participants developed incident dementia. Compared with low levels, high EN-RAGE level was associated with a higher prevalence of dementia (odds ratio [OR], 3.68 [95% CI, 1.50-8.03]; P = .003), while high S-RAGE level was associated with a lower prevalence of dementia (OR, 0.37 [95% CI, 0.17-0.78]; P = .01). These associations attenuated in a longitudinal setting, with hazard ratios of 0.65 (95% CI, 0.42-1.01) for high EN-RAGE (P = .05) and 1.22 (95% CI, 0.82-1.81) for high S-RAGE (P = .33). Among 2890 participants without dementia (mean [SD] age, 72.5 [9.4] years; 1640 [57%] women), higher skin autofluorescence was associated with lower global cognitive function (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.07 [95% CI, -0.11 to -0.04]), especially among carriers of the APOE ε4 allele (adjusted difference in z score per 1-SD higher skin autofluorescence, -0.15 [95% CI, -0.22 to -0.07]). Conclusions and Relevance: These findings suggest that the AGE-RAGE system is associated with cognitive decline and dementia cross-sectionally but not longitudinally. This indicates either a short-term association or reverse causality. Findings of cross-sectional associations between higher skin autofluorescence and lower cognitive function and an association with APOE status also warrant replication and prospective studies.

Dietary Advanced Glycation End-Products (dAGEs) Intake and Bone Health: A Cross-Sectional Analysis in the Rotterdam Study.

Animal studies suggest a role for dietary advanced glycation end-products (dAGEs) in bone health, but human studies on dAGEs in relation to bone are lacking. We aimed to study whether dAGEs intake is associated with the parameters of bone strength namely, bone mineral density (BMD), prevalent vertebral (VFs), and major osteoporotic fractures (MOFs = hip, wrist, proximal humerus, and clinical VFs). 3949 participants (mean age 66.7 ± 10.5 years) were included from a Rotterdam study for whom Carboxymethyllysine (CML-a dietary AGE) was estimated from food frequency questionnaires combined with dAGEs databases. Multivariable linear and logistic regression models were performed adjusting for age, sex, energy intake, dietary quality, physical activity, diabetes, smoking, renal function, and cohort effect and for models on fractures, subsequently for BMD. We observed no association of CML with BMD at both femoral neck (ß = -0.006; p = 0.70) and lumbar spine (ß = -0.013; p = 0.38). A higher intake of CML was linearly associated with VFs (Odds ratio, OR = 1.16, 95% CI (1.02-1.32) and a similar but non-significant trend with MOFs (OR = 1.12 (0.98-1.27). Additional adjustment for BMD did not change the associations. Our results imply a positive association between dietary intake of CML and VFs independent of BMD. Future studies are needed in order to elucidate whether associations found are causal.

The association between dietary and skin advanced glycation end products: the Rotterdam Study.

BACKGROUND: Advanced glycation end products (AGEs) accumulate in tissues with age and in conditions such as diabetes mellitus and chronic kidney disease (CKD), and they may be involved in age-related diseases. Skin AGEs measured as skin autofluorescence (SAF) are a noninvasive reflection of long-term AGE accumulation in tissues. Whether AGEs present in the diet (dAGEs) contribute to tissue AGEs is unclear. OBJECTIVES: Our aim was to investigate the association between dietary and skin AGEs in the Rotterdam Study, a population-based cohort of mainly European ancestry. METHODS: In 2515 participants, intake of 3 dAGEs [carboxymethyl-lysine (CML), N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1), and carboxyethyl-lysine (CEL)] was estimated using FFQs and the content of AGEs measured in commonly consumed foods. SAF was measured 5 y (median value) later using an AGE Reader. The association of dAGEs with SAF was analyzed in linear regression models and stratified for diabetes and chronic kidney disease (CKD, defined as estimated glomerular filtration rate ≤60 mL/min) status. RESULTS: Mean ± SD intake was 3.40 ±0.89 mg/d for CML, 28.98 ±7.87 mg/d for MGH1, and 3.11 ±0.89 mg/d for CEL. None of them was associated with SAF in the total study population. However, in stratified analyses, CML was positively associated with SAF after excluding both individuals with diabetes and individuals with CKD: 1 SD higher daily CML intake was associated with a 0.03 (95% CI: 0.009, 0.05) arbitrary units higher SAF. MGH1 and CEL intake were not significantly associated with SAF. Nevertheless, the associations were stronger when the time difference between dAGEs and SAF measurements was shorter. CONCLUSIONS: Higher dietary CML intake was associated with higher SAF only among participants with neither diabetes nor CKD, which may be explained by high AGE formation in diabetes and decreased excretion in CKD or by dietary modifications in these disease groups. The dAGE-SAF associations were also modified by the time difference between measurements. Our results suggest that dAGEs can influence tissue AGE accumulation and possibly thereby age-related diseases. This trial was registered at the Netherlands National Trial Register as NTR6831 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831) and at the WHO International Clinical Trials Registry Platform as NTR6831 (http://www.who.int/ictrp/network/primary/en/).

Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study.

Advanced glycation end-products (AGEs), which bind to type 1 collagen in bone and skin, have been implicated in reduced bone quality. The AGE reader™ measures skin autofluorescence (SAF), which might be regarded as a marker of long-term accumulation of AGEs in tissues. We investigated the association of SAF with bone mineral density (BMD) and fractures in the general population. We studied 2853 individuals from the Rotterdam Study with available SAF measurements (median age, 74.1 years) and with data on prevalent major osteoporotic (MOFs: hip, humerus, wrist, clinical vertebral) and vertebral fractures (VFs: clinical + radiographic Genant's grade 2 and 3). Radiographs were assessed 4 to 5 years before SAF. Multivariate regression models were performed adjusted for age, sex, BMI, creatinine, smoking status, and presence of diabetes and additionally for BMD with interaction terms to test for effect modification. Prevalence of MOFs was 8.5% and of VFs 7%. SAF had a curvilinear association with prevalent MOFs and VFs and therefore, age-adjusted, sex stratified SAF quartiles were used. The odds ratio (OR) (95% confidence interval [CI]) of the second, third and fourth quartiles of SAF for MOFs were as follows: OR 1.60 (95% CI, 1.08-2.35; p = .02); OR 1.30 (95% CI, 0.89-1.97; p = .20), and OR 1.40 (95% CI, 0.95-2.10; p = .09), respectively, with first (lowest) quartile as reference. For VFs the ORs were as follows: OR 1.69 (95% CI, 1.08-2.64; p = .02), OR 1.74(95% CI, 1.11-2.71; p = .01), and OR 1.73 (95% CI, 1.12-2.73; p = .02) for second, third, and fourth quartiles, respectively. When comparing the top three quartiles combined with the first quartile, the OR (95% CI) for MOFs was 1.43 (95% CI, 1.04-2.00; p = .03) and for VFs was 1.72 (95% CI, 1.18-2.53; p = .005). Additional adjustment for BMD did not change the associations. In conclusion, there is evidence of presence of a threshold of skin AGEs below which there is distinctly lower prevalence of fractures. Longitudinal analyses are needed to confirm our cross-sectional findings. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Diabetes Mellitus-Related Fractional Glucose Uptake in Men and Women Imaged With 18F-FDG PET-CT.

CONTEXT: Cohort studies show that cognitive dysfunction and both vascular and Alzheimer's dementia are more common in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: To review and compare brain volume and 18F-fluorodeoxyglucose (FDG) uptake in brain of individuals age 60 to 70 years with or without type 2 diabetes. DESIGN: We searched 620 medical records for negative 18FDG PET-CT scans obtained during 33 months. Records showing history of cognitive impairment, Alzheimer's disease, neurologic disorders, any history of brain atrophy, or documented cerebral infarction on neuroimaging were excluded from the study. RESULTS: A total of 119 medical records met the inclusion criteria. Data from 63 women and 56 men (without T2DM, 86; with T2DM, 33) were analyzed. Brain volume was larger in men than women (mean ± SD, 1411 ± 225 cm3 vs 1325 ± 147 cm3, respectively; P = 0.02), but men had a significantly lower fractional glucose uptake (SUVgluc), calculated as fasting blood glucose × SUVmax. [median (minimum, maximum), 63.6 (34.6, 126.6) vs 70.0 (36.4, 134.3); P = 0.02]. Brain volume was also larger in persons without T2DM than in those with T2DM (1392 ± 172 cm3 vs 1269 ± 183 cm3; P < 0.001), but SUVgluc was similar between these groups. Brain volume correlated with SUVgluc in both men and women overall (P < 0.001) but not in men and women with T2DM (P = 0.20 and 0.36, respectively). CONCLUSION: In men without T2DM, median brain volume was larger and fractional glucose uptake was less than in women without T2DM. In men and women with T2DM, brain volume and fractional glucose uptake were similar. The findings support the hypothesis that fractional glucose uptake becomes impaired in men with T2DM.