Competitive Tendering In The Netherlands: Central Planning Or Functional Specifications?

Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Ionenstroeme in Thylakoiden

SIGLEAvailable from TIB Hannover: MA 6626 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

PET Imaging of Cerebral Nicotinic Acetylcholine Receptors (nAChRs) in Early Alzheimer’s Disease (AD) Assessed with the New Radioligand (–)-[18F]Norchloro-Fluoro-Homoepibatidine ((–)-[18F]Flubatine)

Objectives: Post mortem studies have shown a degeneration of cholinergic neurons in the brain of AD-patients. Further evidence suggests that the loss of nAChRs is a major contributor to the cognitive deterioration in AD, whereby the alpha4beta2-nAChR subtype is thought to be the most severely reduced in the onset of AD. Using 2-[18F]F-A85380 PET we showed a significant decline in alpha4beta2-nAChRs in early AD-patients which correlated significantly with the loss of cognitive function (Sabri et al. 2008; Kendziorra et al. 2010). However, this tracer was not well suited as a biomarker in a routine clinical set-up for early AD-diagnosis because of unfavourable properties (slow kinetics, long acquisition times up to 7 hours, limited alpha4beta2-receptor-selectivity). We, therefore developed the new radiotracer (-)-[18F]NCFHEB (denominated as [18F]Flubatine) which is an epibatidine derivative with low toxicity in humans), with significantly improved brain uptake, nAChR affinity and selectivity (Brust et al. 2008). Here, we present the results of the worldwide first ongoing [18F]Flubatine-PET study in humans. Methods: 16 mild AD-patients (NINCDS-ADRDA, age 74.4±6.6, MMSE 23.7±2.8) and 11 age-matched healthy controls (HC, age 69.6±5.1, MMSE 28.5±0.9) underwent [18F]Flubatine-PET (370 MBq, 3D-acquisition, ECAT Exact HR+). All were nonsmokers and naïve for central acting medication. In each subject, 4 scans (41 frames) were acquired from 0-270 min post injection and motion correction was performed with SPM2. Kinetic modeling was applied to the VOI-based tissue-activity curves generated for 29 brain regions (irregularly anatomically defined via MRI-coregistration) using a one tissue compartment model with measured arterial input-function. Total distribution volume (DV) and binding potential (BP, reference region: corpus callosum) were used to characterize specific binding. Additionally, parametric images of DV were computed (Logan plot). Results: Image quality of [18F]Flubatine scans was clearly superior to 2-[18F]F-A85380, and a 20 minutes scan already adequate for visual analysis. All 29 regions were well described with one tissue compartment. PET data acquired over only 90 minutes were sufficient to estimate all kinetic parameters of all VOIs (30 minutes sufficient for modelling of all cortical VOIs respectively) precisely indicating a fast binding kinetic (much faster than for 2-[18F]F-A85380). DVs in HCs increase as expected with receptor density: Corpus callosum (DV: 5.32±0,66), temporal (8.92±0.45), posterior cingulate (9.03±0.55), pons (10.97±0.95), thalamus (24.92±3.56). The AD-patients showed significant BP reductions in distinct cortical regions (p<0.05) compared to HCs. Conclusions: Due to significant shorter acquisition time, higher brain uptake, faster kinetics and superior image quality [18F]Flubatine appears to be a much more valuable tracer than 2-[18F]F-A85380 to image alpha4beta2-nAChRs in humans. Furthermore, full kinetic modelling (1-tissue compartment model) is accurately possible within 90 minutes in all VOIs, and within 30 minutes in all cortical VOIs. In keeping with its diagnostic properties, early AD-patients show declines of alpha4beta2-nAChRs in distinct cortical regions typically affected by AD-pathology. These results indicate that Flubatine-PET could have a great potential to be tested as a biomarker for early AD-diagnosis

Cerebral Nicotinic Acetylcholine Receptors (nAChRs) In EarlyAlzheimer’s Disease (AD) Assessed With The New Radioligand [18F]Flubatine and PET

Objectives: There is evidence from post‐mortem studies that the loss of nAChRs, in particular of the alpha4beta2‐nAChR, which is obviously most severely reduced at the onset of AD, is a major contributor to the cognitive deterioration in AD. Accordingly, using 2‐[18F]F‐A85380 PET we showed significant declines in alpha4beta2‐nAChRs in early AD‐patients (Sabri et al. 2008; Kendziorra et al. 2010). However, this tracer was not well suited as a biomarker in a routine clinical set‐up for early AD‐diagnosis because of unfavourable properties (especially long acquisition times up to 7 hours). We, therefore, developed the new radiotracer (‐)‐ [18F]NCFHEB (denominated as [18F]Flubatine) with significantly improved brain uptake and also better nAChR affinity and selectivity (Brust et al. 2008). Here, we present the results of the worldwide first ongoing [18F]Flubatine‐PET study in humans. Methods: 19 mild AD‐patients (NINCDS‐ADRDA, age 74.5±6.2, MMSE 23.7±2.7) and 20 age‐matched healthy controls (HC, age 70.6±4.6, MMSE 28.5±0.8) underwent [18F]Flubatine‐PET (370 MBq, 3D‐acquisition, ECAT Exact HR+, 4 scans, 0‐270 min p.i., motion correction with SPM2). All were nonsmokers and naïve for central acting medication. Kinetic modeling was applied to the VOI‐based tissueactivity curves generated for 29 brain regions. Total distribution volume (DV) and binding potential (BP, reference region: corpus callosum) were used to characterize specific binding. Additionally, parametric images of DV were computed (Logan plot). Results: Image quality of [18F]Flubatine scans was clearly superior to 2‐[18F]FA85380, and a 20 minutes scan already adequate for visual analysis. PET data acquired over only 90 minutes were sufficient to estimate all kinetic parameters of all VOIs with 1‐tissue compartment model. Thirty‐minute scans were already sufficient for modelling of all cortical VOIs. Tracer distribution was similar to known alpha4beta2‐nAChR distribution and DVs in HCs increase as expected with receptor density with the lowest DV in the corpus callosum (5.64±0,87) and highest in the thalamus (24.67±3.91). The AD‐patients showed significant BP reductions in distinct cortical regions (p<0.05) compared to HCs. Conclusions: Due to significant faster kinetics and shorter acquisition time enabling full kinetic modeling within 90 minutes, and superior image quality [18F]Flubatine appears to be a much more suitable tracer than 2‐[18F]F‐A85380 to image alpha4beta2‐nAChRs in humans. In keeping with its diagnostic properties, early AD‐patients show declines of alpha4beta2‐nAChRs in distinct cortical regions typically affected by AD‐pathology. These results indicate that [18F]Flubatine‐PET could have a great potential to be tested as a biomarker for early AD‐diagnosis