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1.
Neuroimage Clin ; 27: 102294, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32570206

RESUMO

OBJECTIVE: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies such as Parkinson's disease (PD). Positron emission tomography (PET) with 18F-FDG reveals metabolic perturbations, which are scored by spatial covariance analysis. However, the resultant pattern scores do not capture the spatially heterogeneous trajectories of metabolic changes between individual brain regions. Assuming metabolic progression occurs as a continuum from the healthy control (HC) condition to iRBD and then PD, we investigated spatial dynamics of progressively perturbed glucose metabolism in a cross-sectional study. METHODS: 19 iRBD patients, 38 PD patients and 19 HC subjects underwent 18F-FDG PET. The images were spatially normalized, scaled to the global mean uptake, and automatically parcellated. We contrasted regional metabolism by group, and allocated the inferred progression to one of several possible trajectories. We further investigated the correlations between 18F-FDG uptake and the disease duration in the iRBD and PD groups, respectively. We also explored relationships between 18F-FDG uptake and the Unified Parkinson's Disease Rating Scale motor (UPDRS III) scores in the PD group. RESULTS: PD patients exhibited more extensive relative hyper- and hypo-metabolism than iRBD patients. We identified three dynamic metabolic trajectories, cross-sectional hypo- or hypermetabolism, cross-sectionally unchanged hypo- or hypermetabolism, cross-sectionally late hypo- or hypermetabolism, appearing only in the contrast of PD with iRBD. No correlation was found between relative 18F-FDG metabolism and disease duration in the iRBD group. Regional hyper- and hypo-metabolism in the PD patients correlated with disease duration or clinical UPDRS III scores. CONCLUSION: Cerebral metabolism changes heterogeneously in a continuum extending from HC to iRBD and PD groups in this preliminary study. The distinctive metabolic trajectories point towards a potential neuroimaging biomarker for conversion of iRBD to frank PD, which should be amenable to advanced pattern recognition analysis in future longitudinal studies.

2.
ACS Appl Mater Interfaces ; 12(22): 24531-24543, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32378873

RESUMO

Polymeric micelles are typically characterized as core-shell structures. The hydrophobic core is considered as a depot for hydrophobic molecules, and the corona-forming block acts as a stabilizing and solubilizing interface between the core and aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of micelles, whereas the role of hydrophilic blocks is rarely investigated in this context, with poly(ethylene glycol) (PEG) being the gold standard of hydrophilic polymers. To better understand the role of the hydrophilic corona, a small library of structurally similar A-B-A-type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s is investigated by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (pMeOx; A) or poly(2-ethyl-2-oxazoline) (pEtOx; A*). In terms of hydrophilicity, both polymers closely resemble PEG. The more hydrophobic block B bears either a poly(2-oxazoline) and poly(2-oxazine) backbone with C3 (propyl) and C4 (butyl) side chains. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* is observed for the formulation with two poorly water-soluble compounds, curcumin and paclitaxel, highlighting the importance of the hydrophilic corona of polymer micelles used for drug formulation. The formulations are also characterized by various nuclear magnetic resonance spectroscopy methods, dynamic light scattering, cryogenic transmission electron microscopy, and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important, but previously largely ignored, factor for the rational design of polymeric micelles.

3.
ACS Appl Mater Interfaces ; 12(11): 12445-12456, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32142257

RESUMO

Amphiphilic block copolymers that undergo (reversible) physical gelation in aqueous media are of great interest in different areas including drug delivery, tissue engineering, regenerative medicine, and biofabrication. We investigated a small library of ABA-type triblock copolymers comprising poly(2-methyl-2-oxazoline) as the hydrophilic shell A and different aromatic poly(2-oxazoline)s and poly(2-oxazine)s cores B in an aqueous solution at different concentrations and temperatures. Interestingly, aqueous solutions of poly(2-methyl-2-oxazoline)-block-poly(2-phenyl-2-oxazine)-block-poly(2-methyl-2-oxazoline) (PMeOx-b-PPheOzi-b-PMeOx) undergo inverse thermogelation below a critical temperature by forming a reversible nanoscale wormlike network. The viscoelastic properties of the resulting gel can be conveniently tailored by the concentration and the polymer composition. Storage moduli of up to 110 kPa could be obtained while the material retains shear-thinning and rapid self-healing properties. We demonstrate three-dimensional (3D) printing of excellently defined and shape-persistent 24-layered scaffolds at different aqueous concentrations to highlight its application potential, e.g., in the research area of biofabrication. A macroporous microstructure, which is stable throughout the printing process, could be confirmed via cryo-scanning electron microscopy (SEM) analysis. The absence of cytotoxicity even at very high concentrations opens a wide range of different applications for this first-in-class material in the field of biomaterials.

4.
Eur J Nucl Med Mol Imaging ; 46(10): 2163-2168, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31289907

RESUMO

PURPOSE: To investigate the in vivo correlation between 18F-fluoroethyl-tyrosine (18F-FET) uptake and amino acid transporter expression and vascularization in treatment-naive glioblastomas. METHODS: A total of 43 stereotactic biopsies were obtained from 13 patients with suspected glioblastoma prior to therapy. All patients underwent a dynamic 18F-FET PET/MRI scan before biopsy. Immunohistochemistry was performed using antibodies against SLC7A5 (amino acid transporter), MIB-1 (Ki67, proliferation), CD31 (vascularization) and CA-IX (hypoxia). The intensity of staining was correlated with 18F-FET uptake and the dynamic 18F-FET uptake slope at the biopsy target point. RESULTS: In all patients, the final diagnosis was IDH-wildtype glioblastoma, WHO grade IV. Static 18F-FET uptake was significantly correlated with SLC7A5 staining (r = 0.494, p = 0.001). While the dynamic 18F-FET uptake slope did not show a significant correlation with amino acid transporter expression, it was significantly correlated with the number of CD31-positive vessels (r = -0.350, p = 0.031), which is line with earlier results linking 18F-FET kinetics with vascularization and perfusion. Besides, static 18F-FET uptake also showed correlations with CA-IX staining (r = 0.394, p = 0.009) and CD31 positivity (r = 0.410, p = 0.006). While the correlation between static 18F-FET uptake and SLC7A5 staining was confirmed as significant in multivariate analysis, this was not the case for the correlation with CD31 positivity, most likely because of the lower effect size and the relatively low number of samples. No significant correlation between 18F-FET uptake and Ki67 proliferation index was observed in our cohort. CONCLUSION: Our results support the findings of preclinical studies suggesting that specific 18F-FET uptake in glioblastomas is mediated by amino acid transporters. As proposed previously, dynamic 18F-FET parameters might be more influenced by perfusion and therefore related to properties of the tumour neovascularization.

5.
PLoS One ; 14(7): e0216111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31339892

RESUMO

BACKGROUND AND PURPOSE: The advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs). PATIENTS AND METHODS: Combined PET-MRI with the tracer O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (MRGTVs). BTVs were semi-automatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and MRGTVs were fused into union volume PET-MRGTVs. The Sørensen-Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the MRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the PET-MRGTVs with margins of 10, 8, 5 and 3 mm. RESULTS: Seven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median MRGTV volume 41.8 cc. Median BTV volume was 36.6 cc and median PET-MRGTV volume 59.3 cc. The median Sørensen-Dice coefficient for the comparison between MRGTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the PET-MRGTV with a reduced margin of 3 mm. CONCLUSION: PET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning.


Assuntos
Bevacizumab/administração & dosagem , Neoplasias Encefálicas , Quimiorradioterapia , Glioma , Imagem por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Temozolomida/administração & dosagem , Tirosina/análogos & derivados , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Feminino , Glioma/diagnóstico por imagem , Glioma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Carga Tumoral , Tirosina/administração & dosagem
6.
Thyroid ; 29(7): 979-992, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30938231

RESUMO

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers, with a median survival of only three to six months. Standard treatment options and even targeted therapies have so far failed to improve long-term overall survival. Thus, novel treatment modalities for ATC, such as immunotherapy, are urgently needed. CD47 is a "don't eat me" signal, which prevents cancer cells from phagocytosis by binding to signal regulatory protein alpha on macrophages. So far, the role of macrophages and the CD47-signal regulatory protein alpha signaling axis in ATC is not well understood. Methods: This study analyzed 19 primary human ATCs for macrophage markers, CD47 expression, and immune checkpoints by immunohistochemistry. ATC cell lines and a fresh ATC sample were assessed by flow cytometry for CD47 expression and macrophage infiltration, respectively. CD47 was blocked in phagocytosis assays of co-cultured macrophages and ATC cell lines. Anti-CD47 antibody treatment was administered to ATC cell line xenotransplanted immunocompromised mice, as well as to tamoxifen-induced ATC double-transgenic mice. Results: Human ATC samples were heavily infiltrated by CD68- and CD163-expressing tumor-associated macrophages (TAMs), and expressed CD47 and calreticulin, the dominant pro-phagocytic molecule. In addition, ATC tissues expressed the immune checkpoint molecules programmed cell death 1 and programmed death ligand 1. Blocking CD47 promoted the phagocytosis of ATC cell lines by macrophages in vitro. Anti-CD47 antibody treatment of ATC xenotransplanted mice increased the frequency of TAMs, enhanced the expression of macrophage activation markers, augmented tumor cell phagocytosis, and suppressed tumor growth. In double-transgenic ATC mice, CD47 was expressed on tumor cells, and blocking CD47 increased TAM frequencies. Conclusions: Targeting CD47 or CD47 in combination with programmed cell death 1 may potentially improve the outcomes of ATC patients and may represent a valuable addition to the current standard of care.

7.
Acta Crystallogr A Found Adv ; 75(Pt 2): 307-313, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30821263

RESUMO

The atomically resolved real-space structure of a long-range-ordered dodecagonal quasicrystal is determined based on scanning tunnelling microscopy. For the BaTiO3-derived oxide quasicrystal which spontaneously forms on a Pt(111) surface, 8100 atomic positions have been determined and are compared with an ideal Niizeki-Gähler tiling. Although the Niizeki-Gähler tiling has a complex three-element structure, the abundance of the triangle, square and rhomb tiling elements in the experimental data closely resembles the ideal frequencies. Similarly, the frequencies of all possible next-neighbour tiling combinations are, within the experimental uncertainty, identical to the ideal tiling. The angular and orientational distributions of all individual tiling elements show the characteristics of the dodecagonal quasicrystal. In contrast, the analysis of the orientation of characteristic and more complex tiling combinations indicates the partial decomposition of the quasicrystal into small patches with locally reduced symmetry. These, however, preserve the long-range quasicrystal coherence. The symmetry reduction from dodecagonal to sixfold is assigned to local interaction with the threefold substrate. It leads to atomic flips which preserve the number of quasicrystal tiling elements.

8.
Eur J Intern Med ; 59: 84-90, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30072202

RESUMO

OBJECTIVES: Blood urea nitrogen (BUN) has been shown to independently predict short- and intermediate-term outcomes in patients with acute myocardial infarction (AMI). We aimed to assess the additive predictive value of BUN beyond estimated glomerular filtration rate (eGFR) in AMI patients with an 8.6-year follow-up. METHODS: This retrospective, observational single-centre study included 1332 consecutive AMI patients (median age 64 years, 58.4% male). BUN, creatinine and eGFR were determined at hospital admission. RESULTS: During a median follow-up of 8.6 years (interquartile range [IQR] 4.0-11.6), 408 patients (30.6%) experienced the study endpoint of cardiovascular mortality. BUN (median 17.0 mg/dL [IQR 13.5-22.7]) was a significant predictor of cardiovascular mortality in univariate Cox regression (hazard ratio (HR) per 1 standard deviation increase 2.10, 95% confidence interval [CI] 1.94-2.28, p < .001). This association remained significant after multivariable adjustment for demographics, clinical variables and eGFR (adjusted HR 1.52 [CI 1.16-2.00, p = .003]). The association between BUN and outcome was more pronounced in patients with eGFR >60 mL/min/1.73m2 (HR 2.81 [CI 2.20-3.58, p < .001]). The discriminatory abilities (Harrell's C-statistic) for BUN, eGFR and creatinine were 0.75, 0.76 and 0.67, respectively. The addition of BUN to eGFR significantly improved the C-statistic (0.78, p for comparison = 0.017), net reclassification (23.7%, p < .001) and integrated discrimination (2.9%, p < .001). CONCLUSIONS: Circulating BUN on admission is an independent predictor of long-term cardiovascular mortality in AMI patients and adds predictive power beyond eGFR. BUN reflects not only kidney function, but also acute haemodynamic and neurohumoral alterations during AMI, and may help to identify high-risk patients.


Assuntos
Nitrogênio da Ureia Sanguínea , Taxa de Filtração Glomerular , Rim/fisiopatologia , Infarto do Miocárdio/mortalidade , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Áustria/epidemiologia , Biomarcadores/sangue , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Estudos Retrospectivos , Análise de Sobrevida
9.
Mar Environ Res ; 143: 101-110, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30477876

RESUMO

To estimate the contribution of a Mya arenaria population to total oxygen utilization (TOU) at different temperatures, the respiration rate of M. arenaria was measured for a full size range at 5 and 15 °C. In this study we measured respiration rates in a closed system while the clams were burrowed in sandy sediment, resembling their natural habitat. Rates were measured over a sufficient time span (24 h) to average varying activity phases during the measurements. We calculated a size-dependent respiration rate for M. arenaria and its variation with temperature. Temperature strongly affects the total population respiration and the contribution of different size classes to respiration of the total M. arenaria population. M. arenaria was estimated to contribute up to 70% to the total oxygen utilization of benthic communities analyzed in this study very much depending on the size distribution of the bivalve population present. Given a specific size distribution, smaller individuals had a stronger influence on the total oxygen utilization at colder temperature, while the influence of larger individuals grew with warmer temperature. Even though sizes contribute differently, a significant relation between abundance and respiration could be drawn in most cases analyzed. However, this relation should not be used as a general rule, but when estimating a population's metabolism the size distribution within that population has to be regarded.


Assuntos
Sedimentos Geológicos/química , Mya , Animais , Biologia Marinha , Mya/anatomia & histologia , Mya/fisiologia , Oxigênio , Consumo de Oxigênio , Respiração , Temperatura
10.
J Clin Med ; 7(12)2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477196

RESUMO

BACKGROUND: Recent evidence suggested levels of aspartate aminotransferase (AST), alanine transaminase (ALT), and AST/ALT ratio (De-Ritis ratio) were associated with a worse outcome after acute myocardial infarction (AMI). However, their value for predicting long-term prognosis remained unknown. Therefore, we investigated the prognostic potential of transaminases on patient outcome after AMI from a long-term perspective. METHODS: Data of a large AMI registry including 1355 consecutive patients were analyzed. The Cox regression hazard analysis was used to assess the impact of transaminases and the De-Ritis ratio on long-term mortality. RESULTS: The median De-Ritis ratio for the entire study population was 1.5 (interquartile range [IQR]: 1.0⁻2.6). After a median follow-up time of 8.6 years, we found that AST (crude hazard ratio (HR) of 1.19 per 1-SD [95% confidence interval (CI): 1 .09⁻1.32; p < 0.001]) and De-Ritis ratio (crude HR of 1.31 per 1-SD [95% CI: 1.18⁻1.44; p < 0.001]), but not ALT (p = 0.827), were significantly associated with long-term mortality after AMI. After adjustment for confounders independently, the De-Ritis ratio remained a strong and independent predictor for long-term mortality in the multivariate model with an adjusted HR of 1.23 per 1-SD (95% CI: 1.07⁻1.42; p = 0.004). Moreover, the De-Ritis ratio added prognostic value beyond N-terminal pro-B-Type Natriuretic Peptide, Troponin T, and Creatine Kinase. CONCLUSION: The De-Ritis ratio is a strong and independent predictor for long-term mortality after AMI. As a readily available biomarker in clinical routine, it might be used to identify patients at risk for fatal cardiovascular events and help to optimize secondary prevention strategies after AMI.

11.
Mol Psychiatry ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30464328

RESUMO

The author listing has been updated to indicate that Timo Grimmer and Kuangyu Shi are equally contributing authors.

12.
Mol Psychiatry ; 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120417

RESUMO

18F-FIBT, 2-(p-Methylaminophenyl)-7-(2-[18F]fluoroethoxy)imidazo-[2,1-b]benzothiazole, is a new selective PET tracer under clinical investigation to specifically image ß-amyloid depositions (Aß) in humans in-vivo that binds to Aß with excellent affinity (Kd 0.7 ± 0.2) and high selectivity over tau and α-synuclein aggregates (Ki > 1000 nM). We aimed to characterize 18F-FIBT in a series of patients with different clinical-pathophysiological phenotypes and to compare its binding characteristics to the reference compound PiB. Six patients (mild late-onset and moderate early-onset AD dementia, mild cognitive impairment due to AD, intermediate likelihood, mild behavioral variant of frontotemporal dementia, subjective memory impairment without evidence of neurodegeneration, and mild dementia due to Posterior Cortical Atrophy) underwent PET imaging with 18F-FIBT on PET/MR. With the guidance of MRI, PET images were corrected for partial volume effect, time-activity curves (TACs) of regions of interest (ROIs) were extracted, and non-displaceable binding potentials (BPnd), standardized uptake value ratios (SUVR), and distribution volume ratio (DVR) were compared. Specific binding was detected in the cases with evidence of the AD pathophysiological process visualized in images of BPnd, DVR and SUVR, consistently with patterns of different tracers in previous studies. SUVR showed the highest correlation with clinical severity. The previous preclinical characterization and the results of this case series suggest the clinical usefulness of FIBT as a selective and highly affine next-generation 18F-labeled tracer for amyloid-imaging with excellent pharmacokinetics in the diagnosis of neurodegenerative diseases. The results compare well to the gold standard PiB and hence support further investigation in larger human samples.

13.
Environ Pollut ; 242(Pt B): 1777-1786, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30076054

RESUMO

Despite of their ubiquitous distribution in marine sediments, the role of benthic fauna in microplastic transport at the sea floor has received little attention yet. The present study investigated the influence of bioturbation activity of the polychaete Arenicola marina on microplastic transport and burial in marine sediments. Sediment ingestion was assessed in a long term mesocosm experiment with exposure times ranging from 106 to 240 days, using three particle tracers with different particle diameters (microplastic: 500 and 1000 µm, respectively; luminophores: 130 µm). Sediment grain size distributions were assessed after experiment termination in all feeding layers at 8-12 cm depth to determine the influence of size-selective feeding of A. marina on median grain size and microplastic retention. Burial of microplastic occurred in all mesocosms up to a depth of 20 cm and was strongly dependent on individual sediment feeding rates. For low bioturbation conditions, both microplastic and luminophore concentrations exhibited an exponential decrease with increasing sediment depth, indicating particle burial via feeding funnel transport. Particle concentrations remained high in the uppermost 4 cm of the sediment. At high bioturbation rates, no microplastic particles remained in near-surface sediment layers, but a distinct accumulation of microplastic was observed in the feeding layer, suggesting the discrimination of plastic particles during feeding. In contrast, luminophores displayed a similar accumulation, but additionally showed uniform distributions above feeding layers, indicating ingestion and defecation by polychaetes. In accordance with these findings, an overall coarsening of median grain sizes was observed in all feeding layers, indicating the retention of large microplastic due to size-selective feeding. These findings demonstrate the ability of the conveyor belt-feeding polychaete A. marina to promote unidirectional transports of microplastic ≥500 µm and the potential for the long-term retention of these particles in marine sediments.


Assuntos
Sedimentos Geológicos/química , Plásticos/análise , Poliquetos/fisiologia , Poluentes Químicos da Água/análise , Animais , Comportamento Animal
14.
Radiology ; 288(1): 198-206, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29762090

RESUMO

Purpose To compare PET/MR hypoperfusion and hypometabolism in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) compared with healthy control (HC) participants. Materials and Methods Maps of cerebral blood flow (CBF; pulsed arterial spin-labeling [ASL] MRI), glucose metabolism (fluorine 18 [18F] fluorodeoxyglucose [FDG] PET), and gray matter (GM) volume (structural T1-weighted MRI) were calculated from integrated PET/MR data in 45 patients with AD (mean age, 69 years ± 9 [standard deviation]; age range, 51-89 years), 20 patients with MCI (mean age, 64 years ± 10; age range, 45-82 years), and 11 HC participants (mean age, 65 years ± 8; age range, 54-80 years) between 2011 and 2014. After preprocessing, voxel-wise analyses of variance, volume of interest, and independent component analyses were performed for comparisons of CBF and glucose metabolism. Results Analyses revealed high overlap between components, regional and quantitative hypoperfusion, and hypometabolism in patients with AD compared with HC participants in precuneus, parietal, temporal, and occipital cortex. In patients with MCI compared with HC participants, FDG PET exclusively demonstrated quantitative hypometabolism and a component in the precuneus. Volume-of-interest analysis in global GM in patients with AD compared with HC participants showed lower CBF (42 mL/100 g per minute ± 8 vs 49 mL/100 g per minute ± 7, respectively; P = .035) and lower FDG uptake (0.8 ± 0.1 vs 1 ± 0.1, respectively; P < .001). Conclusion In patients with AD, pulsed ASL MRI revealed regional and quantitative abnormalities and components similar to 18F-FDG PET with a reduced extent. In patients with MCI, 18F-FDG PET exclusively demonstrated quantitative hypometabolism and a component in the precuneus, indicating higher sensitivity to detect preclinical AD compared with the currently used pulsed ASL MRI sequence.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Fluordesoxiglucose F18 , Imagem por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Compostos Radiofarmacêuticos , Marcadores de Spin
15.
Alzheimers Dement ; 14(7): 913-924, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29601787

RESUMO

INTRODUCTION: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid ß (Aß) pathology. METHODS: We included 3451 Aß+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. RESULTS: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aß+ cognitively normal and Aß+ mild cognitive impairment (P < .05) but not in Aß+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education. DISCUSSION: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aß pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Disfunção Cognitiva/metabolismo , Idoso , Alelos , Biomarcadores/líquido cefalorraquidiano , Europa (Continente) , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Prevalência
16.
Lancet Neurol ; 17(3): 241-250, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29397305

RESUMO

BACKGROUND: Models of Alzheimer's disease propose a sequence of amyloid ß (Aß) accumulation, hypometabolism, and structural decline that precedes the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. In this study, we aimed to characterise where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. METHODS: Between Jan 1, 2009, and Dec 31, 2015, we analysed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer's Network. We analysed 11C-Pittsburgh Compound B (11C-PiB) PET, 18F-Fluorodeoxyglucose (18F-FDG) PET, and structural MRI data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years to symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. This study is registered at ClinicalTrials.gov (number NCT00869817) FINDINGS: 11C-PiB PET was available for 346 individuals (162 with longitudinal imaging), 18F-FDG PET was available for 352 individuals (175 with longitudinal imaging), and MRI data were available for 377 individuals (201 with longitudinal imaging). We found a sequence to pathological changes, with rates of Aß deposition in mutation carriers being significantly different from those in non-carriers first (across regions that showed a significant difference, at a mean of 18·9 years [SD 3·3] before expected onset), followed by hypometabolism (14·1 years [5·1] before expected onset), and lastly structural decline (4·7 years [4·2] before expected onset). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region for each method to show divergence between groups (22·2 years before expected onset for Aß accumulation, 18·8 years before expected onset for hypometabolism, and 13·0 years before expected onset for cortical thinning). INTERPRETATION: Mutation carriers had elevations in Aß deposition, reduced glucose metabolism, and cortical thinning compared with non-carriers which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aß, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials. FUNDING: US National Institutes of Health, the German Center for Neurodegenerative Diseases, and the Medical Research Council Dementias Platform UK.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Mapeamento Encefálico , Encéfalo/diagnóstico por imagem , Saúde da Família , Adulto , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Compostos de Anilina/farmacocinética , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Presenilina-1/genética , Presenilina-2/genética , Estatísticas não Paramétricas , Tiazóis/farmacocinética
17.
NMR Biomed ; 30(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28805936

RESUMO

Hypoxia plays an important role for the prognosis and therapy response of cancer. Thus, hypoxia imaging would be a valuable tool for pre-therapeutic assessment of tumor malignancy. However, there is no standard validated technique for clinical application available yet. Therefore, we performed a study in 12 patients with high-grade glioma, where we directly compared the two currently most promising techniques, namely the MR-based relative oxygen extraction fraction (MR-rOEF) and the PET hypoxia marker H-1-(3-[18 F]-fluoro-2-hydroxypropyl)-2-nitroimidazole ([18 F]-FMISO). MR-rOEF was determined from separate measurements of T2 , T2 * and relative cerebral blood volume (rCBV) employing a multi-parametric approach for quantification of the blood-oxygenation-level-dependent (BOLD) effect. With respect to [18 F]-FMISO-PET, besides the commonly used late uptake between 120 and 130 min ([18 F]-FMISO120-130 min ), we also analyzed the hypoxia specific uptake rate [18 F]-FMISO-k3 , as obtained by pharmacokinetic modeling of dynamic uptake data. Since pharmacokinetic modeling of partially acquired dynamic [18 F]-FMISO data was sensitive to a low signal-to-noise-ratio, analysis was restricted to high-uptake tumor regions. Individual spatial analyses of deoxygenation and hypoxia-related parameter maps revealed that high MR-rOEF values clustered in (edematous) peritumoral tissue, while areas with high [18 F]-FMISO120-130 min concentrated in and around active tumor with disrupted blood-brain barrier, i.e. contrast enhancement in T1 -weighted MRI. Volume-of-interest-based correlations between MR-rOEF and [18 F]-FMISO120-130 min as well as [18 F]-FMISO-k3 , and voxel-wise analyses in individual patients, yielded limited correlations, supporting the notion that [18 F]-FMISO uptake, even after 2 h, might still be influenced by perfusion while [18 F]-FMISO-k3 was severely hampered by noise. According to these results, vascular deoxygenation, as measured by MR-rOEF, and severe tissue hypoxia, as measured by [18 F]-FMISO, show a poor spatial correspondence. Overall, the two methods appear to rather provide complementary than redundant information about high-grade glioma biology.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Hipóxia Celular , Glioma/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Idoso , Feminino , Humanos , Aumento da Imagem , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Misonidazol/análogos & derivados
19.
J Phys Condens Matter ; 29(13): 134002, 2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28140368

RESUMO

We report on the formation of a SrTiO3-derived dodecagonal oxide quasicrystal (OQC) at the interface to Pt(1 1 1). This is the second observation of a two-dimensional quasicrystal in the class of oxides. The SrTiO3-derived OQC exhibits strong similarities to the BaTiO3-derived OQC with respect to the local tiling geometry. However, the characteristic length scale of the SrTiO3-derived OQC is 1.8% smaller. Coexisting with the OQC a large scale approximant structure with a monoclinic unit cell is identified. It demonstrates the extraordinary level of complexity that oxide approximant structures can reach.

20.
Neuroimage ; 146: 589-599, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27693611

RESUMO

OBJECTIVES: In brain 18F-FDG PET data intensity normalization is usually applied to control for unwanted factors confounding brain metabolism. However, it can be difficult to determine a proper intensity normalization region as a reference for the identification of abnormal metabolism in diseased brains. In neurodegenerative disorders, differentiating disease-related changes in brain metabolism from age-associated natural changes remains challenging. This study proposes a new data-driven method to identify proper intensity normalization regions in order to improve separation of age-associated natural changes from disease related changes in brain metabolism. METHODS: 127 female and 128 male healthy subjects (age: 20 to 79) with brain18F-FDG PET/CT in the course of a whole body cancer screening were included. Brain PET images were processed using SPM8 and were parcellated into 116 anatomical regions according to the AAL template. It is assumed that normal brain 18F-FDG metabolism has longitudinal coherency and this coherency leads to better model fitting. The coefficient of determination R2 was proposed as the coherence coefficient, and the total coherence coefficient (overall fitting quality) was employed as an index to assess proper intensity normalization strategies on single subjects and age-cohort averaged data. Age-associated longitudinal changes of normal subjects were derived using the identified intensity normalization method correspondingly. In addition, 15 subjects with clinically diagnosed Parkinson's disease were assessed to evaluate the clinical potential of the proposed new method. RESULTS: Intensity normalizations by paracentral lobule and cerebellar tonsil, both regions derived from the new data-driven coherency method, showed significantly better coherence coefficients than other intensity normalization regions, and especially better than the most widely used global mean normalization. Intensity normalization by paracentral lobule was the most consistent method within both analysis strategies (subject-based and age-cohort averaging). In addition, the proposed new intensity normalization method using the paracentral lobule generates significantly higher differentiation from the age-associated changes than other intensity normalization methods. CONCLUSION: Proper intensity normalization can enhance the longitudinal coherency of normal brain glucose metabolism. The paracentral lobule followed by the cerebellar tonsil are shown to be the two most stable intensity normalization regions concerning age-dependent brain metabolism. This may provide the potential to better differentiate disease-related changes from age-related changes in brain metabolism, which is of relevance in the diagnosis of neurodegenerative disorders.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Processamento de Sinais Assistido por Computador , Adulto Jovem
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