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- Chiotis, Konstantinos
(författare)
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Molecular imaging of tau in the pathological cascade of Alzheimer’s disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pathology of Alzheimer’s disease (AD) is characterised by the misfolding and aggregation of amyloid-β (Aβ) into extracellular plaques and aggregation of tau into intracellular neurofibrillary tangles. Recent advances in molecular imaging have allowed the development of positron emission tomography (PET) tracers for the in vivo detection of Aβ plaques while current efforts focus on the evaluation of recently proposed tracers targeting tau pathology. This thesis is composed of three main parts. Part one compares two Aβ PET tracers ([11C]PIB and [18F]florbetapir) when administered to different but matched patient cohorts, and explores the effect of age on the distribution of Aβ-positive PET scans. Part two focuses on the first in vivo evaluation of the tau-specific tracer [18F]THK5317, using a longitudinal multi-modal design, in a sample of cognitively normal volunteers, patients at different clinical stages of AD and individual patients with atypical parkinsonism. The third part describes the direct in vivo comparison of the binding properties of two tau-specific tracers ([11C]THK5351 and [11C]PBB3) when injected into the same patients with AD on the same day. The results indicated that, firstly, the binding of the Aβ-specific PET tracers, [11C]PIB and [18F]florbetapir, was highly comparable in individuals from different cohorts. Furthermore, age plays an important role in the distribution of Aβ-positive PET scans, with the oldest old patients with cognitive complaints appearing to benefit substantially from clinical assessment with Aβ PET. Secondly, the tracer [18F]THK5317 detected the expected load and regional distribution of tau pathology in vivo in a sample of patients with AD and patients with atypical parkinsonism. The distribution of [18F]THK5317 binding differed from that of Aβ deposition in patients with AD, although regional correlations existed, indicating areas where Aβ and tau pathologies were co-located. The regional load of tau pathology ([18F]THK5317) was associated with measures of global cognition and episodic memory, with local hypometabolism playing a mediating role in this relationship. Longitudinally, a heterogeneous pattern of changes was observed in the binding of the tau tracer [18F]THK5317 in patients with AD, in contrast to the homogeneous changes in glucose metabolism that better tracked cognitive deterioration. The build-up of tau pathology ([18F]THK5317) and the development of local hypometabolism appeared temporally dissociated, with a stronger relationship detected between the two when hypometabolism changes became more prevalent, in the later stages of the disease. Finally, different tau-specific tracers ([11C]THK5351 and [11C]PBB3) seemed to bind in vivo to different molecular targets; [11C]PBB3 binding appeared to correlate closer to Aβ deposition, while [11C]THK5351 binding followed the expected regional pattern of tau pathology in AD and related closer to downstream markers of the disease. Further investigation of the existing PET tracers and development of new tracers is required for shedding light on the pathological processes that contribute to neurodegeneration in AD and for developing clinical markers that allow early and highly accurate discrimination between different proteinopathies.
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| 2. |
- Iaccarino, Leonardo, et al.
(författare)
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A Cross-Validation of FDG- and Amyloid-PET Biomarkers in Mild Cognitive Impairment for the Risk Prediction to Dementia due to Alzheimer's Disease in a Clinical Setting
- 2017
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 59:2, s. 603-614
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Tidskriftsartikel (refereegranskat)abstract
- Assessments of brain glucose metabolism (F-18-FDG-PET) and cerebral amyloid burden (C-11-PiB-PET) in mild cognitive impairment (MCI) have shown highly variable performances when adopted to predict progression to dementia due to Alzheimer's disease (ADD). This study investigates, in a clinical setting, the separate and combined values of F-18-FDGPET and C-11-PiB-PET in ADD conversion prediction with optimized data analysis procedures. Respectively, we investigate the accuracy of an optimized SPM analysis for F-18-FDG-PET and of standardized uptake value ratio semiquantification for C-11-PiB-PET in predicting ADD conversion in 30 MCI subjects (age 63.57 +/- 7.78 years). Fourteen subjects converted to ADD during the follow-up (median 26.5 months, inter-quartile range 30 months). Receiver operating characteristic analyses showed an area under the curve (AUC) of 0.89 and of 0.81 for, respectively, F-18-FDG-PET and C-11-PiB-PET. F-18-FDG-PET, compared to C-11-PiB-PET, showed higher specificity (1.00 versus 0.62, respectively), but lower sensitivity (0.79 versus 1.00). Combining the biomarkers improved classification accuracy (AUC = 0.96). During the follow-up time, all the MCI subjects positive for both PET biomarkers converted to ADD, whereas all the subjects negative for both remained stable. The difference in survival distributions was confirmed by a log-rank test (p = 0.002). These results indicate a very high accuracy in predicting MCI to ADD conversion of both F-18-FDG-PET and C-11-PiB-PET imaging, the former showing optimal performance based on the SPM optimized parametric assessment. Measures of brain glucose metabolism and amyloid load represent extremely powerful diagnostic and prognostic biomarkers with complementary roles in prodromal dementia phase, particularly when tailored to individual cases in clinical settings.
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| 3. |
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| 4. |
- Rodriguez-Vieitez, Elena, et al.
(författare)
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Comparability of [F-18]THK5317 and [C-11]PIB blood flow proxy images with [F-18]FDG positron emission tomography in Alzheimer's disease
- 2017
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE PUBLICATIONS INC. - 0271-678X .- 1559-7016. ; 37:2, s. 740-749
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Tidskriftsartikel (refereegranskat)abstract
- For amyloid positron emission tomography tracers, the simplified reference tissue model derived ratio of influx rate in target relative to reference region (R-1) has been shown to serve as a marker of brain perfusion, and, due to the strong coupling between perfusion and metabolism, as a proxy for glucose metabolism. In the present study, 11 prodromal Alzheimer's disease and nine Alzheimer's disease dementia patients underwent [F-18]THK5317, carbon-11 Pittsburgh Compound-B ([C-11]PIB), and 2-deoxy-2-[F-18]fluoro-D-glucose ([F-18]FDG) positron emission tomography to assess the possible use of early-phase [F-18]THK5317 and R-1 as proxies for brain perfusion, and thus, for glucose metabolism. Discriminative performance (prodromal vs Alzheimer's disease dementia) of [F-18]THK5317 (early-phase SUVr and R-1) was compared with that of [C-11]PIB (early-phase SUVr and R-1) and [F-18]FDG. Strong positive correlations were found between [F-18]THK5317 (early-phase, R-1) and [F-18]FDG, particularly in frontal and temporoparietal regions. Differences in correlations between early-phase and R-1 ([F-18]THK5317 and [C-11]PIB) and [F-18]FDG, were not statistically significant, nor were differences in area under the curve values in the discriminative analysis. Our findings suggest that early-phase [F-18]THK5317 and R-1 provide information on brain perfusion, closely related to glucose metabolism. As such, a single positron emission tomography study with [F-18]THK5317 may provide information about both tau pathology and brain perfusion in Alzheimer's disease, with potential clinical applications.
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