Contribution of APOE Genetic Variants to Dyslipidemia.

BACKGROUND: apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. METHODS: Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. RESULTS: In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. CONCLUSIONS: APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE. However, more investigation is required to elucidate the significance of rarer variants of apoE.

Early assessment of cardiomyopathy in Duchenne patients by means of longitudinal strain echocardiography.

INTRODUCTION: The diagnosis of Duchenne-linked cardiomyopathy may be challenging. Conventional echocardiographic measurements typically show deterioration beyond the second decade. Global longitudinal strain has been proposed as an earlier marker than left ventricular ejection fraction. MATERIAL AND METHODS: A prospective, observational, cross-sectional, case-control study was carried out. Both Duchenne patients and control subjects underwent transthoracic echocardiogram in order to assess left ventricle function. Bayesian linear regression was the main tool for inference. Age effects were parameterised by means of a spline function because of its simplicity to characterise continuous variables and smooth contributions. The posterior distribution of the marginal age effects was used to assess the earliest age of deterioration of each marker. RESULTS: Sixteen Duchenne patients and twenty-two healthy male subjects were enrolled. On overage, cardiac function measures were found for ejection fraction and longitudinal strain among different groups. Age effects on global longitudinal strain are more reliably found at ages of 6 and above, while ejection fraction starts to deteriorate at an older age. Progressive left ventricular dysfunction in Duchenne patients is one of the key issues and starts at an early age with subtle symptoms. CONCLUSION: This cross-sectional study provides supporting evidence that global longitudinal strain is an earlier marker of disease progression than ejection fraction in Duchenne patients.

Diagnosis of Familial Dysbetalipoproteinemia Based on the Lipid Abnormalities Driven by APOE2/E2 Genotype.

BACKGROUND: Familial dysbetalipoproteinemia (FDBL) is a monogenic disease due to variants in APOE with a highly variable phenotype. Current diagnostic lipid-based methods have important limitations. The objective is twofold: to define characteristics of dysbetalipoproteinemia (DBL) based on the analysis of APOE in patients from a lipid unit and in a sample from the general population, and to propose a screening algorithm for FDBL. METHODS: Lipids and APOE genotype from consecutive unrelated subjects from Miguel Servet University Hospital (MSUH) (n 3603), subjects from the general population participants of the Aragon Workers Health Study (AWHS) (n 4981), and selected subjects from external lipid units (Ext) (n 390) were used to define DBL criteria and to train and validate a screening tool. RESULTS: Thirty-five subjects from MSUH, 21 subjects from AWHS, and 31 subjects from Ext were APOE2/2 homozygous. The combination of non high-density lipoprotein cholesterol (non-HDLc)/apoB 1.7 plus triglycerides/apoB 1.35, in mg/dL (non-HDLc [mmol/L]/apolipoprotein B (apoB) [g/L] 4.4 and triglycerides [mmol/L]/apoB [g/L] 3.5), provided the best diagnostic performance for the identification of subjects with hyperlipidemia and APOE2/2 genotype (sensitivity 100 in the 3 cohorts, and specificity 92.8 [MSUH], 80.9 [AWHS], and 77.6 [Ext]). This improves the performance of previous algorithms. Similar sensitivity and specificity were observed in APOE2/2 subjects receiving lipid-lowering drugs. CONCLUSIONS: The combination of non-HDLc/apoB and triglycerides/apoB ratios is a valuable tool to diagnose DBL in patients with hyperlipidemia with or without lipid-lowering drugs. FDBL diagnosis requires DBL and the presence of a compatible APOE genotype. Most adult APOE2/2 subjects express DBL, making FDBL as common as familial hypercholesterolemia in the population.

Factors associated with the presence of tendon xanthomas in familial hypercholesterolemia.

INTRODUCTION AND OBJECTIVES: Tendon xanthomas (TX) are lipid deposits highly specific to familial hypercholesterolemia (FH). However, there is significant variability in their presentation among FH patients, primarily due to largely unknown causes. Lipoprotein(a) is a well-established independent risk factor for atherosclerotic cardiovascular disease in the general population as well as in FH. Given the wide variability of lipoprotein(a) among FH individuals and the likelihood that TX may result from a proatherogenic and proinflammatory condition, the objective of this study was to analyze the size of TX in the Achilles tendons of FH participants and the variables associated with their presence, including lipoprotein(a) concentration. METHODS: A cross-sectional study was conducted on 377 participants with a molecular diagnosis of heterozygous FH. Achilles tendon maximum thickness (ATMT) was measured using ultrasonography with standardized equipment and procedures. Demographic variables and lipid profiles were collected. A multivariate linear regression model using a log-Gaussian approach was used to predict TX size. Classical cardiovascular risk factors and lipoprotein(a) were included as explanatory variables. RESULTS: The mean low-density lipoprotein cholesterol level was 277mg/dL without lipid-lowering treatment, and the median ATMT was 5.50mm. We demonstrated that age, sex, low-density lipoprotein cholesterol, and lipoprotein(a) were independently associated with ATMT. However, these 4 variables did not account for most the interindividual variability observed (R2=0.205). CONCLUSIONS: TX, a characteristic hallmark of FH, exhibit heterogeneity in their presentation. Interindividual variability can partially be explained by age, male sex, low-density lipoprotein cholesterol, and lipoprotein(a) but these factors account for only 20% of this heterogeneity.

Statistical analysis of relative pose information of subcortical nuclei: application on ADNI data.

Many brain morphometry studies have been performed in order to characterize the brain atrophy pattern of Alzheimer's disease (AD). The earliest studies focused on the volume of particular brain structures, such as hippocampus and entorhinal cortex. Even though volumetry is a powerful, robust and intuitive technique that has yielded a wealth of findings, more complex shape descriptors have been used to perform statistical shape analysis of particular brain structures. However, in shape analysis studies of brain structures the information of the relative pose between neighbor structures is typically disregarded. This work presents a framework to analyse pose information including the following approaches: similarity transformations with either pseudo-Riemannian or left-invariant Riemannian metric, and centered transformations with a bi-invariant Riemannian metric. As an illustration, an analysis of covariance (ANCOVA) and a discrimination analysis were performed on Alzheimer's Disease Neuroimaging Initiative (ADNI) data.

Variations in the shape of the frontobasal brain region in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) emerges during childhood through young adulthood coinciding with the late phases of postnatal brain development when fine remodeling of brain anatomy takes place. Previous research has suggested the existence of subtle anatomical alterations in OCD involving focal volume variations in different brain regions including the frontal lobes and basal ganglia. We investigated whether anatomical changes might also involve variations in the shape of the frontobasal region. A total of 101 OCD patients and 101 control subjects were examined using magnetic resonance imaging. A cross-sectional image highly representative of frontal-basal ganglia anatomy was selected in each individual and 25 reliable anatomical landmarks were identified to assess shape changes. A pixel-wise morphing approach was also used to dynamically illustrate the findings. We found significant group differences for overall landmark position and for most individual landmarks delimiting the defined frontobasal region. OCD patients showed a deformation pattern involving shortening of the anterior-posterior dimension of the frontal lobes and basal ganglia, and enlargement of cerebrospinal fluid spaces around the frontal opercula. In addition, we observed significant correlation of brain tissue shape variation with frontal sinus size. Identification of a global change in the shape of the frontobasal region may further contribute to characterizing the nature of brain alterations in OCD. The coincidence of brain shape variations with morphological changes in the frontal sinus indicates a potential association of OCD to late development disturbances, as the frontal sinus macroscopically emerges during the transition between childhood and adulthood.

Tissue-blood exchange of extravascular longitudinal magnetization with account of intracompartmental diffusion.

The joint effect of both extravascular water diffusion and transcapillary water exchange on the longitudinal magnetisation is evaluated theoretically for tissues with sparse capillary networks (e.g., the brain and myocardium). The spatio-temporal profile of the extravascular longitudinal magnetisation is calculated for the limiting case of a high blood concentration of paramagnetic tracer resulting in negligible intravascular magnetisation, hence in a net flux of magnetisation from the extravascular tissue to its contained blood. A related parameter, termed the effective extravascular depolarised volume, is derived that quantifies the ensuing attenuation of the NMR signal and affords a taxonomy of exchange regimes. It is found that the spatio-temporal pattern of magnetisation decay may deviate strongly from that predicted by chemical exchange models when the rate of transcapillary exchange is limited by slow diffusive transport in the extravascular tissue but reproduces known results in the case of fast extravascular diffusion.

Tensor-based morphometry with stationary velocity field diffeomorphic registration: application to ADNI.

Tensor-based morphometry (TBM) is an analysis technique where anatomical information is characterized by means of the spatial transformations mapping a customized template with the observed images. Therefore, accurate inter-subject non-rigid registration is an essential prerequisite for both template estimation and image warping. Subsequent statistical analysis on the spatial transformations is performed to highlight voxel-wise differences. Most of previous TBM studies did not explore the influence of the registration parameters, such as the parameters defining the deformation and the regularization models. In this work performance evaluation of TBM using stationary velocity field (SVF) diffeomorphic registration was performed in a subset of subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A wide range of values of the registration parameters that define the transformation smoothness and the balance between image matching and regularization were explored in the evaluation. The proposed methodology provided brain atrophy maps with very detailed anatomical resolution and with a high significance level compared with results recently published on the same data set using a non-linear elastic registration method.

Malignancy assessment of brain tumours with magnetic resonance spectroscopy and dynamic susceptibility contrast MRI.

Magnetic resonance imaging (MRI) is the most common and well-established imaging modality for evaluation of intracerebral neoplasms, but there are still some incompletely solved challenges, such as reliable distinction between high- and low-grade tumours, exact delineation of tumour extension, and discrimination between recurrent tumour and radiation necrosis. The aim of this study was to evaluate the contribution of two MRI techniques to non-invasively estimate brain tumour grade. Twenty-four patients referred to MRI examination were analyzed and diagnosed with single intra-axial brain tumour. Lastly, histopathological analysis was performed to verify tumour type. Ten patients presented low-grade gliomas, while the remaining patients showed high-grade tumours, including glioblastomas in eight cases, isolated metastases in four patients and two cases with anaplastic gliomas. MRI examinations were performed on a 1.5-T scanner (Signa, General Electric). The acquisition protocol included the following sequences: saggital T1-weighted localizer, axial T1- and T2-weighted MRI, single-voxel magnetic resonance spectroscopy (MRS), dynamic susceptibility contrast (DSC) MRI and contrast-enhanced T1-weighted MRI. MRS data was analyzed with standard software provided by the scanner manufacturer. The metabolite ratio with the largest significant difference between tumour grades was the choline/creatine (Ch/Cr) ratio with elevated values in high-grade gliomas and metastases. A Ch/Cr ratio equal or larger than 1.55 predicted malignancy grade with 92% sensitivity and 80% specificity. The area under the ROC curve was 0.92 (CI: 95%; 0.81-1). Regarding to perfusion parameters, relative cerebral blood volume (rCBV) maps were estimated from the MR signal intensity time series during bolus passage with two commercial software packages. Two different regions of interest (ROI) were used to evaluate rCBV: lesion centre and perilesional region. All rCBV values were normalized to CBV in a contrallateral normal appearing white matter region. Statistical differences were not found between different tumour types. However, the presence of blood-brain barrier (BBB) damage was illustrated from concentration-time curves calculated in DSC-MRI. A cluster analysis of the time series was used to identify regions with contrast agent extravasation where T1-effects are superimposed to T2-effects. The presence of BBB damage from concentration-time curves was highly correlated with enhancement of post-contrast T1-weighted images and predicted tumour malignancy with a 92% sensitivity and 90% specificity. A large spatial heterogeneity in concentration-time curves was observed from the cluster analysis, supporting the assumption that ROI selection to compute hemodynamic parameters must be done carefully in order to extract robust parameters.

Assessment of QT-measurement accuracy using the 12-lead electrocardiogram derived from EASI leads.

The purpose of the present study is to assess QT-interval measurements from the EASI 12-lead electrocardiogram (ECG) as compared with the standard 12-lead ECG. The QT interval was automatically determined in simultaneously recorded standard and EASI 12-lead ECGs, using a validated wavelet-based delineator. The agreement between the 2 sets of measurements was quantified both on a lead-by-lead basis and a multilead basis with global definitions of QRS onset and T-wave end. The results show that the agreement between QT-interval measurements from the 2 lead systems is acceptable, with negligible mean differences and with correlation coefficients ranging from 0.91 to 0.98 depending on the lead studied. Although the SD shows a clear dependence on the selected lead (ranging from 9.2 to 26.4 milliseconds), differences are within the accepted tolerances for automatic delineation. In a few patients, large differences were found, mainly because of changes in morphology present in both lead systems. QT intervals measured by the multilead approach were considerably more stable than single-lead measurements and resulted in a much better agreement between the 2 lead systems (correlation coefficient, 0.98; QT difference, 1.1 +/- 9.8 milliseconds). Thus, the EASI 12-lead ECG may be used for reliable QT monitoring when the multilead delineation approach is adopted.

Plasma amyloid ß 42/40 ratios as biomarkers for amyloid ß cerebral deposition in cognitively normal individuals.

INTRODUCTION: Plasma amyloid ß (Aß) peptides have been previously studied as candidate biomarkers to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. METHODS: Free and total Aß42/40 plasma ratios (FP42/40 and TP42/40, respectively) were determined using ABtest assays in cognitively normal subjects from the Australian Imaging, Biomarker and Lifestyle Flagship Study. This population was followed-up for 72 months and their cortical Aß burden was assessed with positron emission tomography. RESULTS: Cross-sectional and longitudinal analyses showed an inverse association of Aß42/40 plasma ratios and cortical Aß burden. Optimized as a screening tool, TP42/40 reached 81% positive predictive value of high cortical Aß burden, which represents 110% increase over the population prevalence of cortical Aß positivity. DISCUSSION: These findings support the use of plasma Aß42/40 ratios as surrogate biomarkers of cortical Aß deposition and enrichment tools, reducing the number of subjects submitted to invasive tests and, consequently, recruitment costs in clinical trials targeting cognitively normal individuals.

Wavelet-based event detection in implantable cardiac rhythm management devices.

This paper presents a novel event detector for implantable devices. The algorithm is based on a signal model which describes an event as a linear combination of basis functions. The linear combination involves two fundamental electrogram waveforms represented at different time scales. An efficient, low-complexity detector is developed using the dyadic wavelet transform with integer filter coefficients, and a generalized likelihood ratio test. The results show that reliable detection is obtained at an intermediate signal-to-noise ratio (SNR = 25 dB) for various common noise sources. In terms of probabilities of missed events and false alarms, an over-all performance of 0.7% and 0.1%, respectively, was achieved on electrograms corrupted by the different noise types at an intermediate SNR.

Characterization of repolarization alternans during ischemia: time-course and spatial analysis.

T-wave alternans (TWA) has been linked to increased vulnerability to ventricular fibrillation in different settings including myocardial ischemia. In this study, we propose a methodology for the characterization of TWA induced by transient, regional ischemia. We studied the prevalence, magnitude and spatio-temporal relationship between TWA and ischemia in 95 patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Two electrocardiogram records of each patient, a control recording before PTCA and the PTCA record, were analyzed using a robust, recently proposed method for TWA analysis. The detected episodes were characterized in terms of their time-course, lead distribution and alternans waveform. One third of the patients (33.7%) showed TWA episodes during PTCA. The highest prevalence (51.7%) and amplitude were found in patients with left anterior descendent artery occlusion. The onset of TWA was detected after the first 1-2 min of occlusion, suggesting that some level of ischemia must be attained before TWA arises, while disappearance of TWA following reperfusion was much more rapid. The TWA lead distributions and waveforms showed distinct distributions according to the occluded artery reflecting the regional nature of the TWA phenomenon.

Enhanced real-time ECG coder for packetized telecardiology applications.

A new real-time compression method for electrocardiogram (ECG) signals has been developed based on the wavelet transform approach. The method is specifically adaptable for packetized telecardiology applications. The signal is segmented into beats and a beat template is subtracted from them, producing a residual signal. Beat templates and residual signals are coded with a wavelet expansion. Compression is achieved by selecting a subset of wavelet coefficients. The number of selected coefficients depends on a threshold which has different definitions depending on the operational mode of the coder. Compression performance has been tested using a subset of ECG records from MIT-BIH Arrhythmia database. This method has been designed for real-time packetized telecardiology scenarios both in wired and wireless environments.

Methodological principles of T wave alternans analysis: a unified framework.

Visible T wave alternans (TWA) in the electrocardiogram (ECG) had been regarded as an infrequent phenomenon during the first 80 years of electrocardiography. Nevertheless, computerized analysis changed this perception. In the last two decades, a variety of techniques for automatic TWA analysis have been proposed. These techniques have allowed researchers to detect nonvisible TWA in a wide variety of clinical and experimental conditions. Such studies have recently shown that TWA is related to cardiac instability and increased arrhythmogenicity. Comparison of TWA analysis methods is a difficult task due to the diversity of approaches. In this paper, we propose a unified framework which holds the existing methods. In the light of this framework, the methodological principles of the published TWA analysis schemes are compared and discussed. This framework may have an important role to develop new approaches to this problem.

A wavelet-based ECG delineator: evaluation on standard databases.

In this paper, we developed and evaluated a robust single-lead electrocardiogram (ECG) delineation system based on the wavelet transform (WT). In a first step, QRS complexes are detected. Then, each QRS is delineated by detecting and identifying the peaks of the individual waves, as well as the complex onset and end. Finally, the determination of P and T wave peaks, onsets and ends is performed. We evaluated the algorithm on several manually annotated databases, such as MIT-BIH Arrhythmia, QT, European ST-T and CSE databases, developed for validation purposes. The QRS detector obtained a sensitivity of Se = 99.66% and a positive predictivity of P+ = 99.56% over the first lead of the validation databases (more than 980,000 beats), while for the well-known MIT-BIH Arrhythmia Database, Se and P+ over 99.8% were attained. As for the delineation of the ECG waves, the mean and standard deviation of the differences between the automatic and manual annotations were computed. The mean error obtained with the WT approach was found not to exceed one sampling interval, while the standard deviations were around the accepted tolerances between expert physicians, outperforming the results of other well known algorithms, especially in determining the end of T wave.

Remote processing server for ECG-based clinical diagnosis support.

In this paper, we present the development of a remote server that provides a user-friendly access to advanced electrocardiographic (ECG) signal processing techniques. The prototype supplies telemedicine facilities to doctors for clinical indexes remote computation to support diagnosis through the Internet. The user-friendly interface is based on the selection of the desired ECG signal processing tools on a Web browser window. The centralized structure of the system permits unique and user-independent update and management of the software and, therefore, is especially suitable for remote or rural regions to have access to the new ECG information techniques.

Discrimination of AD and normal subjects from MRI: anatomical versus statistical regions.

This work is a feature-extraction and classification study between Alzheimer's disease (AD) patients and normal subjects. Voxel-wise morphological features of brain MRI are defined as the Jacobian determinants that measure the local volume change between each subject and a given atlas. The goal of this work is to determine the region of interest (ROI) which is best suited for classification. Two types of ROIs are considered: anatomical regions, that were automatically segmented in the atlas (amygdalae, hippocampi and lateral ventricles); and statistical regions, defined from group comparison statistical maps. Classification performance was assessed with five classifiers on 20 pairs of matched training and test groups of subjects from the ADNI database. In this study the statistical masks provided the best classification performance.

Correlation of findings in advanced MRI techniques with global severity scales in patients with Parkinson disease.

RATIONALE AND OBJECTIVES: This work is aimed at determining whether magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) may correlate with disease severity in a series of Parkinson disease (PD) patients. MATERIALS AND METHODS: We recruited a consecutive sample of 39 PD patients in several stages of the disease according to Hoehn and Yahr scale. There were 22 men, and the mean age was 74.5 years (SD 7.5). Disease severity was measured with the Unified Parkinson Disease Rating Scale (UPDRS). All of them underwent ¹H MRS in basal ganglia and the anterior cingulate area, as well as DTI in bilateral substantia nigra. Correlation was made between radiological findings and UPDRS. RESULTS: We found significant negative correlation between UPDRS scores and the Glx (glutamate+glutamine) levels in the right (r = -0.35; P = .03) and the left (r = -0.44; P = .006) lentiform nucleus; as well as with glutamate (r = -0.43; P = .008), the Glx/Cr ratio in the right (r = -0.41; P = .01), and in the left lentiform nucleus (r = -0.36; P = .02). We also found positive correlation between UPDRS scores and DTI in right rostral substantia nigra (r = 0.36; P = .02). Glx was increased in lentiform nucleus and fractional anisotropy was reduced in the rostral SN of subjects with PD in early stages. CONCLUSIONS: The results are consistent with the view that more than half the dopaminergic neurons in the nigrostriatal projection are lost before the onset of PD.

Tensor-based morphometry with mappings parameterized by stationary velocity fields in Alzheimer's disease neuroimaging initiative.

Tensor-based morphometry (TBM) is an analysis technique where anatomical information is characterized by means of the spatial transformations between a customized template and observed images. Therefore, accurate inter-subject non-rigid registration is an essential prerrequisite. Further statistical analysis of the spatial transformations is used to highlight some useful information, such as local statistical differences among populations. With the new advent of recent and powerful non-rigid registration algorithms based on the large deformation paradigm, TBM is being increasingly used. In this work we evaluate the statistical power of TBM using stationary velocity field diffeomorphic registration in a large population of subjects from Alzheimer's Disease Neuroimaging Initiative project. The proposed methodology provided atrophy maps with very detailed anatomical resolution and with a high significance compared with results published recently on the same data set.