[11C]PIB, [18F]FDG and MR imaging in patients with mild cognitive impairment.

PURPOSE: Cortical glucose metabolism, brain amyloid ß accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer's disease (AD). The aim of this study was to compare the prognostic ability of [(11)C]PIB PET, [(18)F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI. METHODS: The study group comprised 29 patients with MCI who underwent [(11)C]PIB PET and MR imaging. Of these, 22 also underwent [(18)F]FDG PET. All subjects were invited back for clinical evaluation after 2 years. RESULTS: During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [(11)C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p < 0.05) predicted conversion to AD. Also reduced [(18)F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p < 0.05), but quantitative hippocampal volumes did not (p > 0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [(11)C]PIB retention in the lateral frontal cortex and [(18)F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other. CONCLUSION: The findings indicate that [(11)C]PIB and [(18)F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI.

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.

Model thrombi formed under flow reveal the role of factor XIII-mediated cross-linking in resistance to fibrinolysis.

BACKGROUND: Activated factor XIII (FXIIIa), a transglutaminase, introduces fibrin-fibrin and fibrin-inhibitor cross-links, resulting in more mechanically stable clots. The impact of cross-linking on resistance to fibrinolysis has proved challenging to evaluate quantitatively. METHODS: We used a whole blood model thrombus system to characterize the role of cross-linking in resistance to fibrinolytic degradation. Model thrombi, which mimic arterial thrombi formed in vivo, were prepared with incorporated fluorescently labeled fibrinogen, in order to allow quantification of fibrinolysis as released fluorescence units per minute. RESULTS: A site-specific inhibitor of transglutaminases, added to blood from normal donors, yielded model thrombi that lysed more easily, either spontaneously or by plasminogen activators. This was observed both in the cell/platelet-rich head and fibrin-rich tail. Model thrombi from an FXIII-deficient patient lysed more quickly than normal thrombi; replacement therapy with FXIII concentrate normalized lysis. In vitro addition of purified FXIII to the patient's preprophylaxis blood, but not to normal control blood, resulted in more stable thrombi, indicating no further efficacy of supraphysiologic FXIII. However, addition of tissue transglutaminase, which is synthesized by endothelial cells, generated thrombi that were more resistant to fibrinolysis; this may stabilize mural thrombi in vivo. CONCLUSIONS: Model thrombi formed under flow, even those prepared as plasma 'thrombi', reveal the effect of FXIII on fibrinolysis. Although very low levels of FXIII are known to produce mechanical clot stability, and to achieve γ-dimerization, they appear to be suboptimal in conferring full resistance to fibrinolysis.

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.

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.