Application of the PredictAD decision support tool to a Danish cohort of patients with Alzheimer's disease and other dementias.

BACKGROUND: The diagnosis of Alzheimer's disease (AD) is based on an ever-increasing body of data and knowledge making it a complex task. The PredictAD tool integrates heterogeneous patient data using an interactive user interface to provide decision support. The aim of this project was to investigate the performance of the tool in distinguishing AD from non-AD dementia using a realistic clinical dataset. METHODS: We retrieved clinical data from a group of patients diagnosed with AD (n = 72), vascular dementia (VaD, n = 30), frontotemporal dementia (FTD, n = 25) or dementia with Lewy bodies (DLB, n = 14) at the Copenhagen Memory Clinic at Rigshospitalet. Three classification methods were applied to the data in order to differentiate between AD and a group of non-AD dementias. The methods were the PredictAD tool's Disease State Index (DSI), the naïve Bayesian classifier and the random forest. RESULTS: The DSI performed best for this realistic dataset with an accuracy of 76.6% compared to the accuracies for the naïve Bayesian classifier and random forest of 67.4 and 66.7%, respectively. Furthermore, the DSI differentiated between the four diagnostic groups with a p value of <0.0001. CONCLUSION: In this dataset, the DSI method used by the PredictAD tool showed a superior performance for the differentiation between patients with AD and those with other dementias. However, the methods need to be refined further in order to optimize the differential diagnosis between AD, FTD, VaD and DLB.

Decreased Gray-White Matter Contrast of [11C]-PiB Uptake in Cognitively Unimpaired Subjects with Severe Obstructive Sleep Apnea.

BACKGROUND: Very recently, cognitively normal, middle-aged adults with severe obstructive sleep apnea (OSA) were shown to have regional cortical amyloid-ß deposits. In the normal brain, amyloid tracer (e.g., [11C]-PiB) uptake is observed in white matter (WM) but not in cortical gray matter (GM), resulting in clear GM-WM contrast. There are no reports on possible changes in this contrast in severe OSA. OBJECTIVES: Evaluate changes in the global [11C]-PiB GM-WM contrast and study if factors reflecting clinical and imaging characteristics are associated with them. DESIGN AND SETTING: Cross-sectional imaging study. PARTICIPANTS: 19 cognitively intact middle-aged (mean 44 years) patients with severe OSA (Apnea-Hypopnea Index >30/h), carefully selected to exclude any other possible factors that could alter brain health. MEASUREMENTS: Detailed neuroimaging (amyloid PET, MRI). Signs of possible alterations in amyloid tracer GM-WM contrast and kinetics were studied with static and dynamic [11C]-PiB PET and WM structures with detailed 3.0T MRI. RESULTS: Static [11C]-PiB PET uptake showed significantly decreased GM-WM contrast in 5 out of 19 patients. This was already clearly seen in visual evaluation and also detected quantitatively using retention indexes. Dynamic imaging revealed decreased contrast due to alterations in trace accumulation in the late phase of [11C]-PiB kinetics. Decreased GM-WM contrast in the late phase was global in nature. MRI revealed no corresponding alterations in WM structures. Importantly, decreased GM-WM contrast was associated with smoking (p = 0.007) and higher Apnea-Hypopnea Index (p = 0.001). CONCLUSIONS: Severe OSA was associated with decreased GM-WM contrast in amyloid tracer uptake, with significant correlation with clinical parameters of smoking and AHI. The results support and further extend the current understanding of the deleterious effect of severe OSA on proper amyloid clearance, possibly reflecting dysfunction of the brain glymphatic system.

Reconstruction of 3-D geometry using 2-D profiles and a geometric prior model.

A method has been developed to reconstruct three-dimensional (3-D) surfaces from two-dimensional (2-D) projection data. It is used to produce individualized boundary element models, consisting of thorax and lung surfaces, for electro- and magnetocardiographic inverse problems. Two orthogonal projections are utilized. A geometrical prior model, built using segmented magnetic resonance images, is deformed according to profiles segmented from projection images. In our method, virtual X-ray images of the prior model are first constructed by simulating real X-ray imaging. The 2-D profiles of the model are segmented from the projections and elastically matched with the profiles segmented from patient data. The displacement vectors produced by the elastic 2-D matching are back projected onto the 3-D surface of the prior model. Finally, the model is deformed, using the back-projected vectors. Two different deformation methods are proposed. The accuracy of the method is validated by a simulation. The average reconstruction error of a thorax and lungs was 1.22 voxels, corresponding to about 5 mm.

Bioelectromagnetic localization of a pacing catheter in the heart.

The accuracy of localizing source currents within the human heart by non-invasive magneto- and electrocardiographic methods was investigated in 10 patients. A non-magnetic stimulation catheter inside the heart served as a reference current source. Biplane fluoroscopic imaging with lead ball markers was used to record the catheter position. Simultaneous multichannel magnetocardiographic (MCG) and body surface potential mapping (BSPM) recordings were performed during catheter pacing. Equivalent current dipole localizations were computed from MCG and BSPM data, employing standard and patient-specific boundary element torso models. Using individual models with the lungs included, the average MCG localization error was 7+/-3 mm, whereas the average BSPM localization error was 25+/-4 mm. In the simplified case of a single homogeneous standard torso model, an average error of 9+/-3 mm was obtained from MCG recordings. The MCG localization accuracies obtained in this study imply that the capability of multichannel MCG to locate dipolar sources is sufficient for clinical purposes, even without constructing individual torso models from x-ray or from magnetic resonance images.

The effect of geometric and topologic differences in boundary element models on magnetocardiographic localization accuracy.

This study was performed to evaluate the changes in magnetocardiographic (MCG) source localization results when the geometry and the topology of the volume conductor model were altered. Boundary element volume conductor models of three patients were first constructed. These so-called reference torso models were then manipulated to mimic various sources of error in the measurement and analysis procedures. Next, equivalent current dipole localizations were calculated from simulated and measured multichannel MCG data. The localizations obtained with the reference models were regarded as the "gold standard." The effect of each modification was investigated by calculating three-dimensional distances from the gold standard localizations to the locations obtained with the modified model. The results show that the effect of the lungs and the intra-ventricular blood masses is significant for deep source locations and, therefore, the torso model should preferably contain internal inhomogeneities. However, superficial sources could be localized within a few millimeters even with nonindividual, so called standard torso models. In addition, the torso model should extend long enough in the pelvic region, and the positions of the lungs and the ventricles inside the model should be known in order to obtain accurate localizations.

Statistical shape model of atria, ventricles and epicardium from short- and long-axis MR images.

We describe a new 3-D statistical shape model of the heart consisting of atria, ventricles and epicardium. The model was constructed by combining information on standard short- and long-axis cardiac MR images. In the model, the variability of the shape was modeled with PCA- and ICA-based shape models as well as with non-parametric landmark probability distributions and a probabilistic atlas. The statistical atlas was built from 25 healthy subjects. The shape model was evaluated by applying it to image segmentation. The probabilistic atlas was found to be superior to the other shape models (P < 0.001) in this study.

Model extraction from magnetic resonance volume data using the deformable pyramid.

A general framework for automatic model extraction from magnetic resonance (MR) images is described. The framework is based on a two-stage algorithm. In the first stage, a geometrical and topological multiresolution prior model is constructed. It is based on a pyramid of graphs. In the second stage, a matching algorithm is described. This algorithm is used to deform the prior pyramid in a constrained manner. The topological and the main geometrical properties of the model are preserved, and at the same time, the model adapts itself to the input data. We show that it performs a fast and robust model extraction from image data containing unstructured information and noise. The efficiency of the deformable pyramid is illustrated on a synthetic image. Several examples of the method applied to MR volumes are also represented.

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models.

Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα(12/13) and Gα(i) were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα(12/13) signalling, regulating cell motility and invasion versus epithelial maturation.

Metabolome in progression to Alzheimer's disease.

Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues.

Follow-up of [11C]PIB uptake and brain volume in patients with Alzheimer disease and controls.

OBJECTIVE: In Alzheimer disease (AD), the accumulation pattern of beta-amyloid over time and its relationship with dementia severity are unclear. We investigated the brain uptake of the amyloid ligand (11)C-labeled Pittsburgh compound B ([(11)C]PIB) and volumetric brain changes over a 2-year follow-up in patients with AD and in aged healthy controls. METHODS: Fourteen patients with AD (mean age 72 years, SD 6.6) and 13 healthy controls (mean age 68 years, SD 5.4) were examined at baseline and after 2 years (patients with AD: mean 2.0 years, SD 0.2; controls: mean 2.1 years, SD 0.6) with [(11)C]PIB PET, MRI, and neuropsychological assessments. [(11)C]PIB uptake was analyzed with a voxel-based statistical method (SPM), and quantitative data were obtained with automated region-of-interest analysis. MRI data were analyzed with voxel-wise tensor-based morphometry. RESULTS: The [(11)C]PIB uptake of the patients with AD did not increase significantly during follow-up when compared with that of the controls. MRI showed progressive brain volume change in the patients with AD, e.g., in the hippocampal region, temporal cortex, and precuneus (p < 0.05). The mean Mini-Mental State Examination score of the patients with AD declined from 24.3 (SD 3.1) at baseline to 21.6 (SD 3.9) at follow-up (p = 0.009). Cognitive decline was also evident in other neuropsychological test results. Baseline neocortical [(11)C]PIB uptake ratios predicted subsequent volumetric brain changes in the controls (r = 0.725, p = 0.005). CONCLUSIONS: The results suggest no (or only little) increase in (11)C-labeled Pittsburgh compound B ([(11)C]PIB) uptake during 2 years of Alzheimer disease progression, despite advancing brain atrophy and declining cognitive performance. Nevertheless, changes in [(11)C]PIB uptake during a longer follow-up cannot be excluded. High cortical [(11)C]PIB uptake may predict ongoing brain atrophy in cognitively normal individuals.

EEG spectral entropy, heart rate, photoplethysmography and motor responses to skin incision during sevoflurane anaesthesia.

BACKGROUND: Analgesia is a part of balanced anaesthesia, but direct indicators of nociception do not exist. We examined the relationship between motor reactions and physiological variables during skin incision in sevoflurane anaesthesia and hypothesized that nociception could be detected and graded by significant changes in these variables. METHODS: Thirty-one women scheduled for abdominal hysterectomy participated in the study. Anaesthesia was induced with fentanyl (1 microg kg(-1)), propofol (1 mg kg(-1)) and sevoflurane. Skin incision was performed 14 min after induction during 1.6% end-tidal sevoflurane anaesthesia without neuromuscular blockade. Electrocardiography (ECG), photoplethysmography (PPG) and electroencephalography (EEG) were registered, and a range of variables was computed from these signals. The postincision values, normalized with respect to their preincision values, of movers vs. non-movers were compared. The variables showing significant differences between movers and non-movers were used to develop a logistic regression equation for the classification of patients into movers or non-movers. RESULTS: Twenty-six patients were eligible for analysis, and 12 (46%) displayed a motor reaction to skin incision (movers). Many ECG, PPG and EEG-related variables showed significant differences between the pre- and postincision periods. The best classification performance, assessed by leave-one-out cross-validation, between movers and non-movers was achieved with the combination of response entropy of EEG, RR-interval and PPG notch amplitude. The corresponding equation yielded 96% correct classification with 90% sensitivity and 100% specificity. The classification performance of any single variable alone was considerably worse. CONCLUSION: Combination of information from different sources may be required for monitoring the adequacy of analgesia during anaesthesia.

Chronic exertional compartment syndrome: MR imaging at 0.1 T compared with tissue pressure measurement.

PURPOSE: To compare low-field-strength magnetic resonance (MR) imaging with intracompartmental tissue pressure measurement for the diagnosis of chronic exertional compartment syndrome. MATERIALS AND METHODS: Thirteen patients suspected clinically of having chronic exertional compartment syndrome in the anterior tibial compartment were studied. MR imaging at 0.1-T and intracompartmental tissue pressure measurements of the anterior tibial compartment were performed before and immediately after standard treadmill exercise. The MR measurements were also obtained in eight anterior tibial compartments of four control subjects without the syndrome. Intracompartmental signal intensity was normalized with the signal intensity from lower leg tissues not affected by the compartment syndrome (subcutaneous fat, tibial bone marrow, or superficial posterior compartment). RESULTS: In the patient group, the relative change from rest to the postexercise state in the normalized MR signal intensity parameter correlated significantly (P < .001) with the respective change in intracompartmental pressure and with the absolute postexercise pressure. In the patients with elevated postexercise intracompartmental pressure, the increase in normalized MR signal intensity from rest to the postexercise state was significantly greater (P < .01) than that in the control subjects or the patients with normal or borderline postexercise intracompartmental pressure. In the latter two groups, the MR results were comparable. CONCLUSION: MR imaging performed at rest and immediately after muscular exercise is a promising method for diagnosing chronic exertional compartment syndrome and assessing its severity.

Nonfluoroscopic localization of an amagnetic stimulation catheter by multichannel magnetocardiography.

This study was performed to: (1) evaluate the accuracy of noninvasive magnetocardiographic (MCG) localization of an amagnetic stimulation catheter; (2) validate the feasibility of this multipurpose catheter; and (3) study the characteristics of cardiac evoked fields. A stimulation catheter specially designed to produce no magnetic disturbances was inserted into the heart of five patients after routine electrophysiological studies. The catheter position was documented on biplane cine x-ray images. MCG signals were then recorded in a magnetically shielded room during cardiac pacing. Noninvasive localization of the catheter's tip and stimulated depolarization was computed from measured MCG data using a moving equivalent current-dipole source in patient-specific boundary element torso models. In all five patients, the MCG localizations were anatomically in good agreement with the catheter positions defined from the x-ray images. The mean distance between the position of the tip of the catheter defined from x-ray fluoroscopy and the MCG localization was 11 +/- 4 mm. The mean three-dimensional difference between the MCG localization at the peak stimulus and the MCG localization, during the ventricular evoked response about 3 ms later, was 4 +/- 1 mm calculated from signal-averaged data. The 95% confidence interval of beat-to-beat localization of the tip of the stimulation catheter from ten consecutive beats in the patients was 4 +/- 2 mm. The propagation velocity of the equivalent current dipole between 5 and 10 ms after the peak stimulus was 0.9 +/- 0.2 m/s. The results show that the use of the amagnetic catheter is technically feasible and reliable in clinical studies. The accurate three-dimensional localization of this multipurpose catheter by multichannel MCG suggests that the method could be developed toward a useful clinical tool during electrophysiological studies.