An Efficient Approach for Differentiating Alzheimer's Disease from Normal Elderly Based on Multicenter MRI Using Gray-Level Invariant Features

Machine learning techniques, along with imaging markers extracted from structural magnetic resonance images, have been shown to increase the accuracy to differentiate patients with Alzheimer''s disease (AD) from normal elderly controls. Several forms of anatomical features, such as cortical volume, shape, and thickness, have demonstrated discriminative capability. These approaches rely on accurate non-linear image transformation, which could invite several nuisance factors, such as dependency on transformation parameters and the degree of anatomical abnormality, and an unpredictable influence of residual registration errors. In this study, we tested a simple method to extract disease-related anatomical features, which is suitable for initial stratification of the heterogeneous patient populations often encountered in clinical data. The method employed gray-level invariant features, which were extracted from linearly transformed images, to characterize AD-specific anatomical features. The intensity information from a disease-specific spatial masking, which was linearly registered to each patient, was used to capture the anatomical features. We implemented a two-step feature selection for anatomic recognition. First, a statistic-based feature selection was implemented to extract AD-related anatomical features while excluding non-significant features. Then, seven knowledge-based ROIs were used to capture the local discriminative powers of selected voxels within areas that were sensitive to AD or mild cognitive impairment (MCI). The discriminative capability of the proposed feature was measured by its performance in differentiating AD or MCI from normal elderly controls (NC) using a support vector machine. The statistic-based feature selection, together with the knowledge-based masks, provided a promising solution for capturing anatomical features of the brain efficiently. For the analysis of clinical populations, which are inherently heterogeneous, this approach could stratify the large amount of data rapidly and could be combined with more detailed subsequent analyses based on non-linear transformation.     

What should the Z-score of native protein structures be?

The Z-score of a protein is defined as the energy separation between the native fold and the average of an ensemble of misfolds in the units of the standard deviation of the ensemble. The Z-score is often used as a way of testing the knowledge-based potentials for their ability to recognize the native fold from other alternatives. However, it is not known what range of values the Z-scores should have if one had a correct potential. Here, we offer an estimate of Z-scores extracted from calorimetric measurements of proteins. The energies obtained from these experimental data are compared with those from computer simulations of a lattice model protein. It is suggested that the Z-scores calculated from different knowledge-based potentials are generally too small in comparison with the experimental values.     

Caractérisation combinée par TEP au 18F-FDG et par IRM des lésions hépatiques dans l’échinococcose alvéolaire

Positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) can be used to evaluate parasitic activity in alveolar echinococcosis (AE) as visualization of host–parasite immune reaction around the lesions. We performed a retrospective interpretation of PET and MR (magnetic resonance) images in 24 patients with AE to compare the results of metabolic imaging to Kodama et al. anatomical classification. All patients underwent hepatic MRI and dual-time point FDG-PET (1 hour and 3 hours after injection), improving sensitivity of standard FDG-PET in AE. The comparison of the images showed perilesional ¹⁸F-FDG uptake in all seven patients with type 1 (multiple microcysts without a solid component) and type 2 (multiple microcysts with a solid component) lesions and in ten of 12 patients with type 3 lesions (a solid component surrounding cysts and microcysts). No abnormal perilesional uptake was observed at standard and delayed PET acquisitions in two of 12 patients with type 3 lesions and in all five patients with type 4 (a solid component without microcysts) and type 5 (a large liquid cavity without microcysts) lesions. Our study demonstrates a strong correlation between anatomical “microcystic” aspect and metabolic activity of AE lesions in 89.5% of cases. Thus, microcysts and metabolic perilesional activity seem correlated to parasite activity, which suggests an important role to combined follow-up of AE patients, through multimodality imaging using MRI and ¹⁸F-FDG-PET scan.     

Optimization of FDG-PET/CT imaging protocol for evaluation of patients with primary and metastatic liver disease

Background

Accurate determination of the extrahepatic extent and intrahepatic distribution of disease is very important in patients with primary and metastatic liver disease for deciding whether a patient receives potentially curable surgery or palliative treatment. Our objective was to evaluate the efficacy of delayed phase FDG-PET/CT imaging in lesion detection and to define its clinical impact compared to triple-phase contrast enhanced CT (CECT).

Methods

30 patients underwent delayed phase FDG-PET/CT imaging (90 min whole body scan followed by a delayed abdominal scan at 120 min). Maximum standard uptake values (SUVs) and SUV ratios between tumor and normal liver parenchyma (T/N) were evaluated. In addition, comparison was made to CECT obtained within 10 days of the FDG-PET/CT to evaluate for lesion concordance within individual liver segments (Couinaud designation).

Results

Sites of primary malignancies included: colorectal (19), breast (3), pancreas (2), lung (2), carcinoid (2), cholangiocarcinoma (1), and hepatocellular carcinoma (1). There was a significant increase in SUV value of liver lesions between early and delayed acquisition (P < 0.001). Although there was not a significant reduction in liver background activity between the two studies, there was a strong increase in T/N ratio (P < 0.001) allowing better lesion detection by visual inspection. New lesions were identified in 5 of the 30 patients, which were not appreciated on the early scan. Delayed phase FDG-PET/CT identified one lesion which was not present on the corresponding CECT. Delayed phase FDG-PET/CT revealed extrahepatic sites of metastases not appreciated on CECT in 6 patients.

Conclusion

Delayed phase FDG-PET/CT protocol improved lesion detectability in primary and metastatic liver disease, revealing new lesions in 17% of the patients. Moreover, FDG-PET/CT identified extrahepatic disease not seen on CECT in 20% of the patients.

     

Estimation of P-values for global alignments of protein sequences.

MOTIVATION: The global alignment of protein sequence pairs is often used in the classification and analysis of full-length sequences. The calculation of a Z-score for the comparison gives a length and composition corrected measure of the similarity between the sequences. However, the Z-score alone, does not indicate the likely biological significance of the similarity. In this paper, all pairs of domains from 250 sequences belonging to different SCOP folds were aligned and Z-scores calculated. The distribution of Z-scores was fitted with a peak distribution from which the probability of obtaining a given Z-score from the global alignment of two protein sequences of unrelated fold was calculated. A similar analysis was applied to subsequence pairs found by the Smith-Waterman algorithm. These analyses allow the probability that two protein sequences share the same fold to be estimated by global sequence alignment. RESULTS: The relationship between Z-score and probability varied little over the matrix/gap penalty combinations examined. However, an average shift of +4.7 was observed for Z-scores derived from global alignment of locally-aligned subsequences compared to global alignment of the full-length sequences. This shift was shown to be the result of pre-selection by local alignment, rather than any structural similarity in the subsequences. The search ability of both methods was benchmarked against the SCOP superfamily classification and showed that global alignment Z-scores generated from the entire sequence are as effective as SSEARCH at low error rates and more effective at higher error rates. However, global alignment Z-scores generated from the best locally-aligned subsequence were significantly less effective than SSEARCH. The method of estimating statistical significance described here was shown to give similar values to SSEARCH and BLAST, providing confidence in the significance estimation. AVAILABILITY: Software to apply the statistics to global alignments is available from http://barton.ebi.ac.uk. CONTACT: geoff@ebi.ac.uk     

Generative FDG-PET and MRI Model of Aging and Disease Progression in Alzheimer's Disease

The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer''s Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation.     

Whole Brain Approaches for Identification of Microstructural Abnormalities in Individual Patients: Comparison of Techniques Applied to Mild Traumatic Brain Injury

Purpose

Group-wise analyses of DTI in mTBI have demonstrated evidence of traumatic axonal injury (TAI), associated with adverse clinical outcomes. Although mTBI is likely to have a unique spatial pattern in each patient, group analyses implicitly assume that location of injury will be the same across patients. The purpose of this study was to optimize and validate a procedure for analysis of DTI images acquired in individual patients, which could detect inter-individual differences and be applied in the clinical setting, where patients must be assessed as individuals.

Materials and Methods

After informed consent and in compliance with HIPAA, 34 mTBI patients and 42 normal subjects underwent 3.0 Tesla DTI. Four voxelwise assessment methods (standard Z-score, “one vs. many” t-test, Family-Wise Error Rate control using pseudo t-distribution, EZ-MAP) for use in individual patients, were applied to each patient’s fractional anisotropy (FA) maps and tested for its ability to discriminate patients from controls. Receiver Operating Characteristic (ROC) analyses were used to define optimal thresholds (voxel-level significance and spatial extent) for reliable and robust detection of mTBI pathology.

Results

ROC analyses showed EZ-MAP (specificity 71%, sensitivity 71%), “one vs. many” t-test and standard Z-score (sensitivity 65%, specificity 76% for both methods) resulted in a significant area under the curve (AUC) score for discriminating mTBI patients from controls in terms of the total number of abnormal white matter voxels detected while the FWER test was not significant. EZ-MAP is demonstrated to be robust to assumptions of Gaussian behavior and may serve as an alternative to methods that require strict Gaussian assumptions.

Conclusion

EZ-MAP provides a robust approach for delineation of regional abnormal anisotropy in individual mTBI patients.     

Effects of recombinant human growth hormone on height and skeletal maturation in growth hormone-deficient children with and without severe pretreatment bone age delay

The relative effects of growth hormone (GH) on GH-deficient (GHD) children with and without severely delayed skeletal maturation prior to treatment are unclear. METHODS: Pre-pubertal GHD children enrolled in the National Cooperative Growth Study were divided into two groups: severe pretreatment BA delay (BA Z-score 相似文献   

Accuracy of target delineation by positron emission tomography-based auto-segmentation methods after deformable image registration: A phantom study

PurposeDiagnostic positron emission tomography and computed tomography (PET/CT) images can be fused to the planning CT images by a deformable image registration (DIR). The aim of this study was to evaluate the standardized uptake value (SUV) and target delineation on deformed PET images.MethodsWe used a cylindrical phantom and removable inserts of four spheres (16–38 mm in diameter) and three ellipsoids with a volume equal to the 38-mm-diameter sphere (S38) in each. S38 was filled with 18F-fluorodeoxyglucose activity, and then PET/CT images were acquired. The contours of S38 were generated using original PET images by PET auto-segmentation (PET-AS) methods of (1) SUV2.5, (2) 40% of maximum SUV (SUV40%max), and (3) gradient-based (GB), and were deformed to the other inserts by DIR. We compared the volumes and the SUV_max with the generated contours using the deformed PET images.ResultsThe SUV_max was slightly decreased by DIR; the mean absolute difference was −0.10 ± 0.04. For SUV2.5 and SUV40%max, the differences in S38 volumes between the original and deformed PET images were less than 5%, regardless of deformation type. For the GB, the contoured volumes obtained from deformed PET images were larger than those of the original PET images for the deformation type of ellipsoids. When the S38 was deformed to the 16-mm-diameter sphere, the maximum volume difference was −22.8%.ConclusionsAlthough SUV fluctuations by DIR were negligible, the target delineation on deformed PET images by the GB should be carefully considered owing to the distortion of intensity profiles.     

A Dynamic Finite Element Analysis of Human Foot Complex in the Sagittal Plane during Level Walking

The objective of this study is to develop a computational framework for investigating the dynamic behavior and the internal loading conditions of the human foot complex during locomotion. A subject-specific dynamic finite element model in the sagittal plane was constructed based on anatomical structures segmented from medical CT scan images. Three-dimensional gait measurements were conducted to support and validate the model. Ankle joint forces and moment derived from gait measurements were used to drive the model. Explicit finite element simulations were conducted, covering the entire stance phase from heel-strike impact to toe-off. The predicted ground reaction forces, center of pressure, foot bone motions and plantar surface pressure showed reasonably good agreement with the gait measurement data over most of the stance phase. The prediction discrepancies can be explained by the assumptions and limitations of the model. Our analysis showed that a dynamic FE simulation can improve the prediction accuracy in the peak plantar pressures at some parts of the foot complex by 10%–33% compared to a quasi-static FE simulation. However, to simplify the costly explicit FE simulation, the proposed model is confined only to the sagittal plane and has a simplified representation of foot structure. The dynamic finite element foot model proposed in this study would provide a useful tool for future extension to a fully muscle-driven dynamic three-dimensional model with detailed representation of all major anatomical structures, in order to investigate the structural dynamics of the human foot musculoskeletal system during normal or even pathological functioning.     

Comparison of lipid binding and kinetic properties of normal, variant, and gamma-carboxyglutamic acid modified human factor IX and factor IXa

The abilities of normal and three abnormal factor IXa molecules to activate factor X and to bind to phospholipid membranes have been compared to define the contributions of protein-lipid interactions and factor IXa light chain-heavy chain interactions to the functioning of this protein. The abnormal proteins studied had altered amino acid residues in their light chains. The heavy-chain regions, containing the active site serine and histidine residues, were normal in the abnormal proteins on the basis of titration by antithrombin III. The binding constants (Kd) for normal (N), variant [Chapel Hill (CH) and Alabama (AL)], and gamma-carboxyglutamic acid (Gla) modified (MOD) factors IX and IXa to phosphatidylserine (PS)/phosphatidylcholine (PC) small, unilamellar vesicles (SUV) were measured by 90 degrees light scattering. The Kd values for factor IXN binding were quite sensitive to the PS content of the membrane but less sensitive to Ca2+ concentrations between 0.5 and 10 mM. The zymogen and activated forms of both normal and abnormal factor IX bound with similar affinities to PS/PC (30/70) SUV. In the cases of factor IXaN and factor IXaAL, but not factor IXaCH or factor IXaMOD, irreversible changes in scattering intensity suggested protein-induced vesicle fusion. Since the activation peptide is not released from factor IXaCH, the normal interaction of factor IXa with a membrane must require the release of the activation peptide and the presence of intact Gla residues. The rate of factor X activation by normal and abnormal factor IXa was obtained by using a chromogenic substrate for factor Xa in the presence of PS/PC (30/70) SUV and 5 mM Ca2+.     

Rational sequence of tests for pancreatic function.

Of 144 patients with suspected pancreatic disease in whom a 75Se-selenomethionine scan was performed, endoscopic retrograde pancreatography (ERP) was successful in 108 (75%). The final diagnosis is known in 100 patients and has been compared with scan and ERP findings. A normal scan reliably indicated a normal pancreas, but the scan was falsely abnormal in 30%. ERP distinguished between carcinoma and chronic pancreatitis in 84% of cases but was falsely normal in five patients with pancreatic disease. In extrahepatic biliary disease both tests tended to give falsely abnormal results. A sequence of tests to provide a rapid and reliable assessment of pancreatic function should be a radio-isotope scan, followed by ERP if the results of the scan are abnormal, and a Lundh test if the scan is abnormal but the findings on ERP are normal.     

Kinematic characteristics of the voluntary cyclic trunk movements in patients at the early stage of Parkinson's disease

Patients with the initial stage of Parkinson disease (PD) and matched controls performed repetitive bendings and turnings in standing position. Tasks included trunk movements in each of the anatomical planes: sagittal, frontal and axial. Electromagnetic system Flock of Birds was used for movement registration. Sensors were fixed at different segments of subject's body. Joint angles in the ankle, hip and torso as well as coordinates of the center of pressure served as output parameters. The amplitudes of joint angles were found to be lower in PD patients. Performance of the axial rotation revealed most pronounced differences. Thus, the amplitudes of joint angles of trunk movements in different anatomical planes reliably discriminate between PD patients and healthy subjects.     

Z-score biological significance of binding hot spots of protein interfaces by using crystal packing as the reference state

Characterization of binding hot spots of protein interfaces is a fundamental study in molecular biology. Many computational methods have been proposed to identify binding hot spots. However, there are few studies to assess the biological significance of binding hot spots. We introduce the notion of biological significance of a contact residue for capturing the probability of the residue occurring in or contributing to protein binding interfaces. We take a statistical Z-score approach to the assessment of the biological significance. The method has three main steps. First, the potential score of a residue is defined by using a knowledge-based potential function with relative accessible surface area calculations. A null distribution of this potential score is then generated from artifact crystal packing contacts. Finally, the Z-score significance of a contact residue with a specific potential score is determined according to this null distribution. We hypothesize that residues at binding hot spots have big absolute values of Z-score as they contribute greatly to binding free energy. Thus, we propose to use Z-score to predict whether a contact residue is a hot spot residue. Comparison with previously reported methods on two benchmark datasets shows that this Z-score method is mostly superior to earlier methods. This article is part of a Special Issue entitled: Computational Methods for Protein Interaction and Structural Prediction.     

Modelling the line of action for the oblique abdominal muscles using an elliptical torso model

When modelling the line of action of a muscle, anatomical considerations must be included if the model is to realistically mimic the muscle behaviour. The internal and external oblique muscles are examples of muscles that do not follow a straight line between origin and insertion, instead having to wrap around the torso. A model is presented which describes the shape of the torso using a right elliptical cylinder of varying dimensions. The muscle lines of action are then calculated based on this underlying torso shape. The model has been successfully fitted to the data reported by Stokes and Gardner-Morse (Journal of Biomechanics 32(3) (1999) 311). When compared to a linear model, the use of the torso model results in a 15% increase in the axial twist moment, and decreases in the lateral bend and extension moments (5% and 2%, respectively), able to be generated by the internal and external oblique muscles combined in upright stance. These differences become larger (up to 37%) when the torso is flexed, extended or twisted. The structure of the torso model allows it to be used to model any posture without significant increases in the overall model complexity.     

Skeletal Scintigraphy

Skeletal scintigraphy, using phosphates or diphosphonates labeled with technetium 99m, is a sensitive method of detecting bone abnormalities. The most important and most frequent role of bone scanning is evaluating the skeletal areas in patients who have a primary cancer, especially a malignant condition that has a tendency to spread to bone areas. The bone scan is superior to bone radiographs in diagnosing these abnormalities; 15 percent to 25 percent of patients with breast, prostate or lung cancer, who have normal roentgenograms, also have abnormal scintigrams due to metastases. The majority of bone metastases appear as hot spots on the scan and are easily recognized. The incidence of abnormal bone scans in patients with early stages (I and II) of breast cancer varies from 6 percent to 26 percent, but almost invariably those patients with scan abnormalities have a poor prognosis and should be considered for additional therapies. Progression or regression of bony lesions can be defined through scanning, and abnormal areas can be identified for biopsy. The incidence of metastases in solitary scan lesions in patients with known primary tumors varies from 20 percent to 64 percent. Bone scintigraphy shows positive uptake in 95 percent of cases with acute osteomyelitis. Stress fractures and trauma suspected in battered babies can be diagnosed by scanning before there is radiological evidence. The procedure is free from acute or long-term side effects and, except in cases of very young patients, sedation is seldom necessary.Although the test is sensitive, it is not specific and therefore it is difficult to overemphasize the importance of clinical, radiographic, biochemical and scanning correlation in each patient.     

Multisegmental image fusion of the spine]

Fusion of medical images is a technique that permits the correlation of homologous anatomical structures in different imaging modalities on the basis of a spatial transformation of the data sets. CT and MRI of the spine provide complementary information of possible relevance for diagnostic and therapeutic decisions. Methods enabling a multisegmental CT-MRI fusion of the spine were developed. These solve the problem of altered spatial relationships of the individual anatomical structures due to differing patient positioning in successive data acquisitions. Routine clinical CT and MRI data of a thoracic section of the spine were obtained and transferred to a PC-workstation. Following segmentation of the CT-data, landmarks for each individual vertebra were defined in the CT and MRI data. For each individual vertebra the algorithm we developed then carried out a rigid registration of the CT information to the MR data. The fused data sets were presented as colour-coded images or on the basis of dynamic variation of transparency. To assess registration precision, fiducial registration errors (FRE) and target registration errors (TRE) were calculated. The algorithm permitted multi-segmental image fusion of the spine. The average time required for defining the landmarks was 22 seconds per landmark for CT, and 34 seconds per landmark for MR. The average FRE was 1.53 mm. The TRE for the vertebrae was less than 2 mm. The colour-coded images were particularly suitable for assessing the contours of the anatomical structures, whereas dynamic variation of the transparency of overlapping CT images enabled a better overall assessment of the spatial relationship of the anatomical structures. The algorithm permits precise multi-segmental fusion of CT and MR of the spine, which was not possible using current fusion-algorithms due to variations in the spatial orientation of the anatomical structures caused by different positioning of the axial skeleton in successive examinations.     

Magnetic Resonance Imaging of the Newborn Brain: Automatic Segmentation of Brain Images into 50 Anatomical Regions

We studied methods for the automatic segmentation of neonatal and developing brain images into 50 anatomical regions, utilizing a new set of manually segmented magnetic resonance (MR) images from 5 term-born and 15 preterm infants imaged at term corrected age called ALBERTs. Two methods were compared: individual registrations with label propagation and fusion; and template based registration with propagation of a maximum probability neonatal ALBERT (MPNA). In both cases we evaluated the performance of different neonatal atlases and MPNA, and the approaches were compared with the manual segmentations by means of the Dice overlap coefficient. Dice values, averaged across regions, were 0.81±0.02 using label propagation and fusion for the preterm population, and 0.81±0.02 using the single registration of a MPNA for the term population. Segmentations of 36 further unsegmented target images of developing brains yielded visibly high-quality results. This registration approach allows the rapid construction of automatically labeled age-specific brain atlases for neonates and the developing brain.     

Three-dimensional reconstruction and characterization of human external shapes from two-dimensional images using volumetric methods

This work presents a volumetric approach to reconstruct and characterise 3D models of external anatomical structures from 2D images. Volumetric methods represent the final volume using a finite set of 3D geometric primitives, usually designed as voxels. Thus, from an image sequence acquired around the object to reconstruct, the images are calibrated and the 3D models of the referred object are built using different approaches of volumetric methods. The final goal is to analyse the accuracy of the obtained models when modifying some of the parameters of the considered volumetric methods, such as the type of voxel projection (rectangular or accurate), the way the consistency of the voxels is tested (only silhouettes or silhouettes and photo-consistency) and the initial size of the reconstructed volume.     

Plasma zinc and copper in Paris area preschool children with growth impairment

Plasma zinc, copper, and parameters of growth were measured in a group of 116 French preschool children, 2–5 yr-old from low-income households. Participants were selected on the basis of Z-scores of weight for height (WHZ) and height for age (HAZ). Zinc and copper concentrations of children with growth impairment (GI), defined by a WHZ and/or HAZ< −1 Z-score, were compared to those of age, sex, and ethnic origin matched controls (WHZ and HAZ >−1 Z-score). Mean (±SD) plasma zinc concentration was 12.58±1.84 μmol/L in the GI group, and 13.27±1.98 μmol/L in the controls. The difference of the means of paired samples was 0.69±2.34, and by pairedt-test the significance reachedp=0.028. This effect was primarily a result of the weight retarded group (WHZ <−1 Z-score,p<0.009) and to the girls (p<0.05). There were no significant differences in plasma copper concentrations between groups. These results suggest the presence of marginal zinc deficiency in French preschool children with low weight for height Z-scores.