Computed tomography predictors of increased transvenous lead extraction difficulty.

BACKGROUND: The ability of computed tomography (CT) characteristics to predict the difficulty of transvenous lead extraction (TLE) is an evolving subject. OBJECTIVE: To identify CT characteristics associated with increased TLE difficulty. METHODS: All consecutive patients undergoing TLE at the University of California San Diego from January 2018 to February 2022 were analyzed, utilizing the UC San Diego Lead Extraction Registry. Patients underwent cardiac-gated chest CT scans with intravenous contrast; all scans were reviewed by a single radiologist. Lead extraction was performed per standard institutional protocol with the initial use of a laser sheath and crossover to a mechanical sheath as needed. Multivariable linear and logistic regression analyses were performed to identify predictors of individual lead-removal fluoroscopy time and mechanical sheath use, as markers of extraction difficulty. RESULTS: A total of 343 patients were analyzed. The mean age of the study population was 63.8 ± 15.4 years; 71% were male. The mean lead dwell-in duration was 8.6 ± 5.7 years. In multivariable linear regression analysis, venous occlusion detected on CT was independently associated with higher individual lead-removal fluoroscopy time (p = 0.004), when adjusting for clinical characteristics such as lead dwell time. In multivariable logistic regression analysis, calcification and venous occlusion were independently associated with a higher need for mechanical sheath use during TLE (odds ratio:5.08, p < 0.001, 95% CI: 2.54-10.46) and (odds ratio:3.72, p < 0.001, 95% CI: 1.89-7.35), respectively. CONCLUSION: In patients undergoing TLE, venous occlusion identified by chest CT is associated with increased fluoroscopy time. Patients with lead-associated calcification or venous occlusion detected by chest CT are each five and three times more likely to require crossover from laser to a mechanical sheath.

Silent Airway Mucus Plugs in COPD and Clinical Implications.

BACKGROUND: Airway mucus plugs are frequently identified on CT scans of patients with COPD with a smoking history without mucus-related symptoms (ie, cough, phlegm [silent mucus plugs]). RESEARCH QUESTION: In patients with COPD, what are the risk and protective factors associated with silent airway mucus plugs? Are silent mucus plugs associated with functional, structural, and clinical measures of disease? STUDY DESIGN AND METHODS: We identified mucus plugs on chest CT scans of participants with COPD from the COPDGene study. The mucus plug score was defined as the number of pulmonary segments with mucus plugs, ranging from 0 to 18, and categorized into three groups (0, 1-2, and ≥ 3). We determined risk and protective factors for silent mucus plugs and the associations of silent mucus plugs with measures of disease severity using multivariable linear and logistic regression models. RESULTS: Of 4,363 participants with COPD, 1,739 had no cough or phlegm. Among the 1,739 participants, 627 (36%) had airway mucus plugs identified on CT scan. Risk factors of silent mucus plugs (compared with symptomatic mucus plugs) were older age (OR, 1.02), female sex (OR, 1.40), and Black race (OR, 1.93) (all P values < .01). Among those without cough or phlegm, silent mucus plugs (vs absence of mucus plugs) were associated with worse 6-min walk distance, worse resting arterial oxygen saturation, worse FEV1 % predicted, greater emphysema, thicker airway walls, and higher odds of severe exacerbation in the past year in adjusted models. INTERPRETATION: Mucus plugs are common in patients with COPD without mucus-related symptoms. Silent mucus plugs are associated with worse functional, structural, and clinical measures of disease. CT scan-identified mucus plugs can complement the evaluation of patients with COPD.

Deep Learning Synthetic Strain: Quantitative Assessment of Regional Myocardial Wall Motion at MRI.

Purpose: To assess the feasibility of a newly developed algorithm, called deep learning synthetic strain (DLSS), to infer myocardial velocity from cine steady-state free precession (SSFP) images and detect wall motion abnormalities in patients with ischemic heart disease. Materials and Methods: In this retrospective study, DLSS was developed by using a data set of 223 cardiac MRI examinations including cine SSFP images and four-dimensional flow velocity data (November 2017 to May 2021). To establish normal ranges, segmental strain was measured in 40 individuals (mean age, 41 years ± 17 [SD]; 30 men) without cardiac disease. Then, DLSS performance in the detection of wall motion abnormalities was assessed in a separate group of patients with coronary artery disease, and these findings were compared with consensus results of four independent cardiothoracic radiologists (ground truth). Algorithm performance was evaluated by using receiver operating characteristic curve analysis. Results: Median peak segmental radial strain in individuals with normal cardiac MRI findings was 38% (IQR: 30%-48%). Among patients with ischemic heart disease (846 segments in 53 patients; mean age, 61 years ± 12; 41 men), the Cohen κ among four cardiothoracic readers for detecting wall motion abnormalities was 0.60-0.78. DLSS achieved an area under the receiver operating characteristic curve of 0.90. Using a fixed 30% threshold for abnormal peak radial strain, the algorithm achieved a sensitivity, specificity, and accuracy of 86%, 85%, and 86%, respectively. Conclusion: The deep learning algorithm had comparable performance with subspecialty radiologists in inferring myocardial velocity from cine SSFP images and identifying myocardial wall motion abnormalities at rest in patients with ischemic heart disease.Keywords: Neural Networks, Cardiac, MR Imaging, Ischemia/Infarction Supplemental material is available for this article. © RSNA, 2023.

Airway-Occluding Mucus Plugs and Mortality in Patients With Chronic Obstructive Pulmonary Disease.

Importance: Airway mucus plugs are common in patients with chronic obstructive pulmonary disease (COPD); however, the association of airway mucus plugging and mortality in patients with COPD is unknown. Objective: To determine whether airway mucus plugs identified on chest computed tomography (CT) were associated with increased all-cause mortality. Design, Setting, and Participants: Observational retrospective analysis of prospectively collected data of patients with a diagnosis of COPD in the Genetic Epidemiology of COPD cohort. Participants were non-Hispanic Black or White individuals, aged 45 to 80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centers across the US between November 2007 and April 2011 and were followed up through August 31, 2022. Exposures: Mucus plugs that completely occluded airways on chest CT scans, identified in medium- to large-sized airways (ie, approximately 2- to 10-mm lumen diameter) and categorized as affecting 0, 1 to 2, or 3 or more lung segments. Main Outcomes and Measures: The primary outcome was all-cause mortality, assessed with proportional hazard regression analysis. Models were adjusted for age, sex, race and ethnicity, body mass index, pack-years smoked, current smoking status, forced expiratory volume in the first second of expiration, and CT measures of emphysema and airway disease. Results: Among the 4483 participants with COPD, 4363 were included in the primary analysis (median age, 63 years [IQR, 57-70 years]; 44% were women). A total of 2585 (59.3%), 953 (21.8%), and 825 (18.9%) participants had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. During a median 9.5-year follow-up, 1769 participants (40.6%) died. The mortality rates were 34.0% (95% CI, 32.2%-35.8%), 46.7% (95% CI, 43.5%-49.9%), and 54.1% (95% CI, 50.7%-57.4%) in participants who had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. The presence of mucus plugs in 1 to 2 vs 0 and 3 or more vs 0 lung segments was associated with an adjusted hazard ratio of death of 1.15 (95% CI, 1.02-1.29) and 1.24 (95% CI, 1.10-1.41), respectively. Conclusions and Relevance: In participants with COPD, the presence of mucus plugs that obstructed medium- to large-sized airways was associated with higher all-cause mortality compared with patients without mucus plugging on chest CT scans.

Reader Perceptions and Impact of AI on CT Assessment of Air Trapping.

Quantitative imaging measurements can be facilitated by artificial intelligence (AI) algorithms, but how they might impact decision-making and be perceived by radiologists remains uncertain. After creation of a dedicated inspiratory-expiratory CT examination and concurrent deployment of a quantitative AI algorithm for assessing air trapping, five cardiothoracic radiologists retrospectively evaluated severity of air trapping on 17 examination studies. Air trapping severity of each lobe was evaluated in three stages: qualitatively (visually); semiquantitatively, allowing manual region-of-interest measurements; and quantitatively, using results from an AI algorithm. Readers were surveyed on each case for their perceptions of the AI algorithm. The algorithm improved interreader agreement (intraclass correlation coefficients: visual, 0.28; semiquantitative, 0.40; quantitative, 0.84; P < .001) and improved correlation with pulmonary function testing (forced expiratory volume in 1 second-to-forced vital capacity ratio) (visual r = -0.26, semiquantitative r = -0.32, quantitative r = -0.44). Readers perceived moderate agreement with the AI algorithm (Likert scale average, 3.7 of 5), a mild impact on their final assessment (average, 2.6), and a neutral perception of overall utility (average, 3.5). Though the AI algorithm objectively improved interreader consistency and correlation with pulmonary function testing, individual readers did not immediately perceive this benefit, revealing a potential barrier to clinical adoption. Keywords: Technology Assessment, Quantification © RSNA, 2021.

Radiologist-supervised Transfer Learning: Improving Radiographic Localization of Pneumonia and Prognostication of Patients With COVID-19.

PURPOSE: To assess the potential of a transfer learning strategy leveraging radiologist supervision to enhance convolutional neural network-based (CNN) localization of pneumonia on radiographs and to further assess the prognostic value of CNN severity quantification on patients evaluated for COVID-19 pneumonia, for whom severity on the presenting radiograph is a known predictor of mortality and intubation. MATERIALS AND METHODS: We obtained an initial CNN previously trained to localize pneumonia along with 25,684 radiographs used for its training. We additionally curated 1466 radiographs from patients who had a computed tomography (CT) performed on the same day. Regional likelihoods of pneumonia were then annotated by cardiothoracic radiologists, referencing these CTs. Combining data, a preexisting CNN was fine-tuned using transfer learning. Whole-image and regional performance of the updated CNN was assessed using receiver-operating characteristic area under the curve and Dice. Finally, the value of CNN measurements was assessed with survival analysis on 203 patients with COVID-19 and compared against modified radiographic assessment of lung edema (mRALE) score. RESULTS: Pneumonia detection area under the curve improved on both internal (0.756 to 0.841) and external (0.864 to 0.876) validation data. Dice overlap also improved, particularly in the lung bases (R: 0.121 to 0.433, L: 0.111 to 0.486). There was strong correlation between radiologist mRALE score and CNN fractional area of involvement (ρ=0.85). Survival analysis showed similar, strong prognostic ability of the CNN and mRALE for mortality, likelihood of intubation, and duration of hospitalization among patients with COVID-19. CONCLUSIONS: Radiologist-supervised transfer learning can enhance the ability of CNNs to localize and quantify the severity of disease. Closed-loop systems incorporating radiologists may be beneficial for continued improvement of artificial intelligence algorithms.

Hemodynamic Assessment of Structural Heart Disease Using 4D Flow MRI: How We Do It.

MRI is an essential diagnostic tool in the anatomic and functional evaluation of cardiovascular disease. In many practices, 2D phase-contrast (2D-PC) MRI has been used for blood flow quantification. Four-dimensional flow MRI is a time-resolved volumetric acquisition that captures the vector field of blood flow along with anatomic images. It also provides a simpler acquisition compared with 2D-PC and facilitates a more accurate and comprehensive hemodynamic assessment. Advancements in accelerated imaging have significantly shortened scanning times for 4D flow MRI while preserving image quality, enabling this technology to transition from the research arena to routine clinical practice. In this article, we review technical optimization based on our more than 10 years of clinical experience with 4D flow MRI. We also present pearls and pitfalls in the practical application of 4D flow MRI, including how to quantify cardiovascular shunts, valvular or vascular stenosis, and valvular regurgitation. As experience increases, and as 4D flow sequences and postprocessing software become more broadly available, 4D flow MRI will likely become an essential component of cardiac imaging in practices involved in the management of congenital and acquired structural heart disease.

Clinical significance of incidentally detected lead perforations by computed tomography.

BACKGROUND: Computed tomography (CT) has an established role in detecting perforation of implanted pacemaker and defibrillator leads. The clinical significance of incidental finding of delayed lead perforation remains unclear. The aim of this study was to assess the prevalence of lead perforation as detected by CT in a cohort of patients undergoing transvenous laser lead extraction and characterize the association between finding of incidental lead perforation with periprocedural outcomes. METHODS: Consecutive patients that underwent chest CT and lead extraction were retrospectively assessed for presence of lead perforation. A total of 143 patients and 348 leads were assessed. The finding of lead perforation was correlated with findings from peri-procedural transesophageal echocardiography (TEE) and outcomes of the lead extraction procedure. RESULTS: Lead perforations (including perforations <5 mm and ≥5 mm) were detected in 66 (46%) patients and 73 (21%) leads. Lead perforation ≥5 mm were less common and detected in 13 (9%) of patients and 14 (4%) of leads. There was no significant difference in the rates of peri-procedural death, cardiac avulsion, cardiac tamponade or post-extraction pericardial effusion in patients with and without lead perforation. CONCLUSIONS: Incidental delayed lead perforations detected by CT are common and do not correlate with significant TEE findings or adverse peri-procedural outcomes in patients undergoing lead extraction. Larger studies are needed to further characterize the frequency and safety of these findings.

Luminal Plugging on Chest CT Scan: Association With Lung Function, Quality of Life, and COPD Clinical Phenotypes.

BACKGROUND: Mucous exudates occluding the lumen of small airways are associated with reduced lung function and mortality in subjects with COPD; however, luminal plugs in large airways have not been widely studied. We aimed to examine the associations of chest CT scan-identified luminal plugging with lung function, health-related quality of life, and COPD phenotypes. METHODS: We randomly selected 100 smokers without COPD and 400 smokers with COPD from the COPDGene Study. Luminal plugging was visually identified on inspiratory CT scans at baseline and 5-year follow-up. The relationships of luminal plugging to FEV1, St. George's Respiratory Questionnaire (SGRQ) score, emphysema on CT scan (defined as the percentage of low attenuation area < 950 Hounsfield units [%LAA-950]), and chronic bronchitis were assessed using linear and logistic multivariable analyses. RESULTS: Overall, 111 subjects (22%) had luminal plugging. The prevalence of luminal plugging was higher in subjects with COPD than those without COPD (25% vs 10%, respectively; P = .001). In subjects with COPD, luminal plugging was significantly associated with FEV1 % predicted (estimate, -6.1; SE, 2.1; P = .004) and SGRQ score (estimate, 4.9; SE, 2.4; P = .04) in adjusted models. Although luminal plugging was associated with log %LAA-950 (estimate, 0.43; SE, 0.16; P = .007), its relationship with chronic bronchitis did not reach statistical significance (P = .07). Seventy-three percent of subjects with COPD with luminal plugging at baseline had it 5 years later. CONCLUSIONS: In subjects with COPD, CT-identified luminal plugging is associated with airflow obstruction, worse health-related quality of life, and emphysema phenotype. This imaging feature may supplement the current clinical assessment of chronic mucus hypersecretion in COPD.

Imaging of Cardiac Support Devices.

Patients hospitalized in the intensive care unit (ICU) often have multiple support lines and devices that need routine imaging evaluation by radiologists. In patients with cardiogenic shock or depressed cardiac function, mechanical circulation support devices are used in combination with medical therapies to improve patient outcomes and sometimes can stabilize patients for surgical intervention. This article discusses some of the more commonly encountered mechanical circulation devices seen in ICU patients, including intra-aortic balloon pumps, Impella devices, extracorporeal membrane oxygenation cannulas, and ventricular assist devices. Normal appearance and commonly encountered device-related complications that can be diagnosed on imaging are reviewed.

Computed Tomography-Guided Risk Assessment in Percutaneous Lead Extraction.

OBJECTIVES: The aim of this study was to assess if pre-procedural computed tomography (CT) could identify high-risk operative features and predict increased procedural complexity. BACKGROUND: Unpredictable lead adhesions can make lead extraction complicated. Adhesions are known to affect leads with longer indwelling time but can unpredictably affect newer leads. METHODS: Consecutive patients who had CTs performed ≤90 days before their planned lead extraction (LE) were included. CTs were reviewed blinded to outcome according to a preset checklist. The outcome was a combined endpoint of procedural complexity and major complications. RESULTS: Between January 1, 2015 and July 1, 2018, 143 patients underwent CT and LE. Median age was 68 years (interquartile range [IQR]: 54.4 to 76.5), and 35% were female. Median age of extracted leads was 111 months, and 126 (43%) were >10 years. CT detected lead perforation ≥5 mm (n = 13), <5 mm (n = 55), severe lead adhesions (n = 65), leads touching vessel wall >1 cm (n = 102), lead fracture (n = 8), and severe ipsilateral venous stenosis/occlusion (n = 36). The procedure was complex in 63 cases. There were 2 deaths, and 6 major complications. Patients with severe lead adhesions had more complex procedures (n = 36 vs 29; p = 0.04), whereas none of the other findings on CT were significantly associated with worse outcome. In patients with leads that had an indwelling time <10 years (n = 72), severe lead adhesions on CT was associated with worse outcome in multivariable analysis (odds ratio: 6.4; 95% confidence interval: 1.4 to 30.2; p = 0.02). CONCLUSIONS: Pre-procedural CT can be used to locate severe lead adhesions in patients planned for lead extraction. In patients with indwelling leads <10 years, pre-procedural CT aids in identifying patients prone to complex extractions.

A retrospective study correlating sonographic features of thyroid nodules with fine-needle aspiration cytology in a South African setting.

BACKGROUND: Thyroid nodules are prevalent worldwide. Detection rates are increasing because of the use of ultrasonography. Ultrasound has become the first-choice imaging modality in evaluating nodules. The decision to perform an US-guided fine-needle aspiration (FNA) is based on a nodule's sonographic features. Thus, it is essential to accurately risk stratify thyroid nodules so that they are appropriately referred for FNA. OBJECTIVES: The aim of this study was to correlate the ultrasound imaging features of thyroid nodules with FNA cytology and surgical histopathology results, and to risk stratify patients using the American Thyroid Association (ATA) classification for each imaging characteristic with the likelihood of the nodule being malignant. METHOD: Retrospective analysis of a thyroid ultrasound database at Chris Hani Baragwanath Academic Hospital, over the period 2015-2017. Frequencies and percentages were used to summarise the data. Univariate logistic regression analyses were used to assess the accuracy of sonographic features in predicting the histologically determined diagnosis for thyroid tumours. RESULTS: A total of 113 nodules underwent FNA, of which 104 were diagnostic. The best three ultrasound features that pose a higher risk for malignancy are absent halo, presence of microcalcifications and hypoechoic appearance. No single nodule feature is an absolute indicator for malignancy. There is a high agreement between ATA classification and cytopathology or histology when nodule features are grouped into clusters. Agreement between the ATA classification and cytopathology/histology was 86.7% with a kappa of 0.714. The agreement between the cytopathology FNA results and lobectomy histopathology was 98.8% with a kappa of 0.973. CONCLUSION: This study contributes to the paucity of data available for sub-Saharan Africa and provides reassurance that our results are consistent with international studies. The study confirms that the usage of a thyroid nodule classification system improves characterisation and increases accuracy in detecting thyroid malignancies, thus sparing many patients the morbidity of unnecessary thyroid surgery.

Immune-Mediated Lung Diseases.

Immune-mediated lung diseases are a complex group of diseases characterized by inflammatory cellular infiltration of the lungs which can result in progressive airway remodeling and parenchymal injury. Diseases have variable presentation depending on antigen exposure, patient predisposition, and type of immune response. Early recognition, removal of the inciting antigen, and steroid intervention are important to prevent disease progression. This article will review key clinical, radiologic, and pathologic features of immune-mediated lung diseases.

Dicarbonyls induce senescence of human vascular endothelial cells.

RATIONALE: Glyoxal (GO) and Methylglyoxal (MGO) are two dicarbonyls involved in the formation of advanced glycation end products (AGEs). Endothelial cells in the vessels are in constant contact with circulating AGEs and dicarbonyls. With this project, we aimed to elucidate the effect of GO and MGO on primary human vascular endothelial cells (HVECs). METHODS: Graft material from patients with coronary heart disease was used as HVECs source. HVECs were treated with different concentrations of GO and MGO. ß-Galactosidase related senescence activity and cell morphology were analyzed. AGEs as well as p21 protein expression, glyoxalase-I expression and oxidative stress were detected. RESULTS: We here provide evidences that GO and MGO induce senescence in primary HVECs. Mechanistically GO and MGO induce senescence by increasing the ROS production, the expression of p21, the accumulation of AGEs and the arrest of HVECs in the G2 cell cycle phase. Aminoguanidine - a dicarbonyl scavenger - abrogated the effect of GO and MGO. CONCLUSION: Our data are relevant as they suggest that in diseases with elevated dicarbonyl concentrations, deleterious effects on the endothelium and the development of vascular dysfunction have to be expected. On the other hand, treatment of patients with dicarbonyl scavenger could prevent this.

Novel insights in the dysfunction of human blood-brain barrier after glycation.

The blood-brain barrier (BBB) provides a dynamic and complex interface consisting of endothelial cells, pericytes and astrocytes, which are embedded in a collagen and fibronectin-rich basement membrane. This complex structure restricts the diffusion of small hydrophilic solutes and macromolecules as well as the transmigration of leukocytes into the brain. It has been shown that carbonyl stress followed by the formation of advanced glycation endproducts (AGE=glycation) interfere with the BBB integrity and function. Here, we present data that carbonyl stress induced by methylglyoxal leads to glycation of endothelial cells and the basement membrane, which interferes with the barrier-function and with the expression of RAGE, occludin and ZO-1. Furthermore, methylglyoxal induced carbonyl stress promotes the expression of the pro-inflammatory interleukins IL-6 and IL-8. In summary, this study provides new insights into the relationship between AGE formation by carbonyl stress and brain microvascular endothelial barrier dysfunction.

Association of Nonalcoholic Fatty Liver Disease With Visceral Adiposity but Not Coronary Artery Calcification in the Elderly.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is related closely to risk factors for coronary artery disease, but it is unclear whether NAFLD independently contributes to atherosclerosis. We investigated the association between NAFLD and coronary artery calcium (CAC) scores, determined based on noncontrast cardiac computed tomography data, in an elderly cohort. METHODS: We conducted a longitudinal, cross-sectional study of data from 250 participants (mean age, 67.6 ± 7.0 y; 43.2% men) in the Rancho Bernardo Study-a prospective population-based study of mostly white adults in suburban Southern California. We compared CAC scores, liver-to-spleen attenuation ratio, and volumes of visceral adipose tissue (VAT) at baseline and after a 5-year follow-up period. RESULTS: We assigned participants to groups based on CAC scores (0, 0-10, 11-100, 101-400, and >400). Among groups, the liver-to-spleen attenuation ratio did not vary significantly, but VAT increased with CAC score (median and interquartile range values were as follows: 50.0 [33.3-77.4] cm(3), 63.0 [33.9-93.1] cm(3), 66.1 [48.2-80.2] cm(3), 69.1 [48.1-85.0] cm(3), 76.1 [53.1-108.5] cm(3) for CAC groups; P = .0054). In multivariable regression analysis, NAFLD at baseline was not associated with an increased risk of a CAC score greater than 0. Longitudinal analysis showed that visceral fat, but not hepatic steatosis, increased in participants with increasing CAC scores (interquartile range 57.1-92.4) vs 55.2 cm(3) in patients without (interquartile range 36.5-81.1, P = .0401). The proportion of patients with NAFLD decreased after the 5-year follow-up period (from 29.3% before to 14.1% afterward; P = .0081), despite increased mean CAC scores and VAT volume in patients. CONCLUSIONS: In adults age 67.6 ± 7.0 years, the proportion with NAFLD decreased despite increasing CAC score and VAT with age. There was no clear association between NAFLD and CAC score. However, VAT was associated with baseline and increasing CAC scores. Visceral adiposity therefore might be a risk factor for coronary artery disease.

Glycation of the high affinity NGF-receptor and RAGE leads to reduced ligand affinity.

AGEs are posttranslational modifications generated by irreversible non-enzymatic crosslinking reactions between sugars and proteins - a reaction referred to as glycation. Glycation, a feature of ageing, can lead to non-degradable and less functional proteins and enzymes and can additionally induce inflammation and further pathophysiological processes such as neurodegeneration. In this study we investigated the influence of glycation on the high affinity NGF-receptor TrkA and the AGE-receptor RAGE. We quantified the binding affinity of the TrkA-receptor and RAGE to their ligands by surface plasmon resonance (SPR) and compared these to the binding affinity after glycation. At the same time, we established a glycation procedure using SPR. We found that glycation of TrkA reduced the affinity to NGF by a factor of three, which could be shown to lead to a reduction of NGF-dependent neurite outgrowth in PC12 cells. Glycation of RAGE reduced binding affinity of AGEs by 10-fold.

Advanced glycation endproducts interfere with adhesion and neurite outgrowth.

Advanced glycation endproducts (AGEs) represent a non-enzymatic posttranslational protein modification. AGEs are generated by a series of chemical reactions of free reducing monosaccharides, such as glucose, fructose or metabolites of the monosaccharide metabolism with amino groups of proteins. After oxidation, dehydration and condensation, stable AGE-modifications are formed. AGE-modified proteins accumulate in all cells and tissues as a normal feature of ageing and correlate with the glucose concentration in the blood. AGEs are increased in diabetic patients and play a significant role in the pathogenesis of most age-related neural disorders, such as Alzheimer's disease. We examined the role of AGEs on neurite outgrowth of PC12 cells. We induced the formation of AGEs using the reactive carbonyl compound methylglyoxal (MGO) as a physiological metabolite of glucose. We found that AGE-modification of laminin or collagen interfered with adhesion but not with neurite outgrowth of PC12 cells. Furthermore, the AGE-modification of PC12 cell proteins reduced NGF-induced neurite outgrowth. In conclusion, our data show that AGEs negatively influence neural plasticity.

Role of advanced glycation end products in cellular signaling.

Improvements in health care and lifestyle have led to an elevated lifespan and increased focus on age-associated diseases, such as neurodegeneration, cardiovascular disease, frailty and arteriosclerosis. In all these chronic diseases protein, lipid or nucleic acid modifications are involved, including cross-linked and non-degradable aggregates, such as advanced glycation end products (AGEs). Formation of endogenous or uptake of dietary AGEs can lead to further protein modifications and activation of several inflammatory signaling pathways. This review will give an overview of the most prominent AGE-mediated signaling cascades, AGE receptor interactions, prevention of AGE formation and the impact of AGEs during pathophysiological processes.