Search result for : author:a t willemsen

Total 7 result(s) found

Crossed Cerebellar Diaschisis in Alzheimer's Disease.

We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer's disease (AD) according to the National Institute on Aging -Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.

F E Reesink, D Vallez Garcia, C A Sanchez-Catasus, D E Peretti, A T Willemsen, R Boellaard, S K Meles, R B Huitema, B M de Jong, R A Dierckx, P P De Deyn
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On the quantification of [18F]MPPF binding to 5-HT1A receptors in the human brain.

Previous studies have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperazine ([(18)F]MPPF) binds with high selectivity to serotonin (5-HT(1A)) receptors in man. However, in these studies, the calculation of the binding potential (BP, which equals receptor density divided by equilibrium dissociation constant) used a metabolite-corrected arterial input. The aim of this study was to determine whether metabolite correction and arterial sampling are essential for the assessment of BP. Five analytic methods using full datasets obtained from 6 healthy volunteers were compared. In addition, the clinical applicability of these methods was appraised. Three methods were based on Logan analysis of the dynamic PET data using metabolite-corrected and uncorrected arterial plasma input and cerebellar input. The other 2 methods consisted of a simplified reference tissue model and standard compartmental modeling. A high correlation was found between BP calculated with Logan analysis using the metabolite-corrected plasma input (used as the reference method for this study) and Logan analysis using either the uncorrected arterial plasma input (r(2) = 0.95, slope = 0.85) or cerebellar input (r(2) = 0.98, slope = 0.91). A high correlation was also found between our reference method and the simplified reference tissue model (r(2) = 0.94, slope = 0.92). In contrast, a poor correlation was observed between our reference method and the standard compartmental model (r(2) = 0.45, slope = 1.59). These results indicate that neither metabolite analysis nor arterial sampling is necessary for clinical evaluation of BP in the human brain with [(18)F]MPPF. Both the Logan analysis method with cerebellar input and the simplified reference tissue method can be applied clinically.

J Passchier, A van Waarde, W Vaalburg, A T Willemsen
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Quantifying drug-related 5-HT1A receptor occupancy with.

There is an increased interest in measuring the interaction of new or established drugs with their targets, in order to gain a better understanding of their mechanisms of action. PET can provide this information if an appropriate radioligand is available. [18F]MPPF (4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine) is a selective radioligand for serotonin 5-HT1A receptors. We have established that the binding potential (BP=Bmax/KD) of [18F]MPPF for cerebral 5-HT1A receptors can be assessed in human brain without arterial sampling. The aim of this study was to assess if 5-HT1A receptor occupancy can be measured through calculation of a drug-related decrease in BP with [18F]MPPF and PET. Six volunteers were scanned twice using a Siemens Exact HR+ camera following injection of 70+/-18 MBq [18F]MPPF (baseline and medicated conditions). Before the second scan, volunteers orally received either 3x10 mg pindolol at T=-15.5 h, T=-6.5 h, and T=-1.5 h (n=3) or 10 mg buspirone in a single dose at T=-1.5 h (n=3). Binding potentials were calculated using the simplified reference tissue model with the cerebellum as reference. Administration of 30 mg pindolol led to a significant reduction in [18F]MPPF binding potential of 42+/-17%. In contrast, no significant reduction of [18F]MPPF binding potential was observed following administration of buspirone (5+/-17%). These results show that [18F]MPPF can be used for measurement of drug-related 5-HT1A receptor occupancy and may be of particular interest in determining the 5-HT1A receptor interaction of new or established drugs in phase 1 and early phase 2 drug trials. Apparently, the 5-HT1A partial agonist buspirone is already clinically effective at low levels of 5-HT1A receptor occupancy.

J Passchier, A van Waarde, R M Pieterman, A T Willemsen, W Vaalburg
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In vivo delineation of 5-HT1A receptors in human brain with [18F]MPPF.

Serotonin-1A (5-hydroxytryptamine-1A [5-HT1A]) receptors have been reported to play an important role in the pathophysiology of a variety of psychiatric and neurodegenerative disorders. Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2'-pyridinyl)-p-[18F]fluorobenzamido ]ethylpiperazine ([18F]MPPF) may be suitable for 5-HT1A receptor imaging in humans. The aim of this study was to determine if [18F]MPPF can be used for the quantitative analysis of 5-HT1A receptor densities in brain regions of healthy human volunteers. [15O]H2O perfusion scanning was performed before intravenous injection of [18F]MPPF to obtain anatomic information. Cerebral radioactivity was monitored using a PET camera. Plasma metabolites of [18F]MPPF were determined by high-performance liquid chromatography. Binding potentials were calculated using the metabolite-corrected arterial input function and a linear graphic method (Logan-Patlak analysis). The highest levels of radioactivity were observed in the medial temporal cortex, especially in the hippocampal area. In contrast, the cerebellum and basal ganglia showed low uptake of 18F, in accordance with known 5-HT1A receptor distribution. The calculated binding potentials correlated well with literature values for 5-HT1A receptor densities. The binding potentials for [18F]MPPF were 4-6 times lower than those that have been reported for [carbonyl-1C]-(N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyrid yl) cyclohexane-carboxamide (WAY 100635), indicating that [18F]MPPF has a lower in vivo affinity for 5-HT1A receptors. These results confirm that [18F]MPPF can be used for the quantitative analysis of 5-HT1A receptor distribution in the living human brain. The rapid dissociation from the receptor makes this ligand a possible candidate to monitor changes in endogenous serotonin levels.

J Passchier, A van Waarde, R M Pieterman, P H Elsinga, J Pruim, H N Hendrikse, A T Willemsen, W Vaalburg
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Quantitative imaging of 5-HT(1A) receptor binding in healthy volunteers with [(18)f]p-MPPF.

Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido+ ++] ethylpiperazine ([(18)F]p-MPPF) can be used for 5-hydroxytryptamine(1A) (5-HT(1A)) receptor imaging. The aim of this study was to develop a method for the quantitative imaging of 5-HT(1A) receptors in healthy volunteers with [(18)F]p-MPPF. After injection of [(18)F]p-MPPF radioactivity was rapidly taken up in the brain, with the highest accumulation in the medial temporal cortex. Low levels of radioactivity were found in cerebellum and basal ganglia. Plasma clearance and metabolism of [(18)F]p-MPPF resulted in only about 1% of the radioactivity in plasma as parent radioligand after 10 min. Using a linear graphical method (Logan-Patlak), binding potentials were calculated in several brain areas. A good correlation (r = 0.95) was found between the obtained binding potentials and literature values for 5-HT(1A) receptor densities. A good correlation (r = 0.96) was also found between the body weight-corrected region/cerebellum ratios and the respective binding potentials. Moreover, a blocking experiment with pindolol (n = 3) showed a decrease of 40% in the region/cerebellum ratios of the target areas. Compared to those of [carbonyl-(11)C]WAY-100635, the binding potentials were four to six times lower, indicating that [(18)F]p-MPPF has a lower in vivo affinity for 5-HT(1A) receptors. In conclusion, [(18)F]p-MPPF can be used for the quantitative analysis of 5-HT(1A) receptor distribution in human brain.

J Passchier, A van Waarde, R M Pieterman, P H Elsinga, J Pruim, H N Hendrikse, A T Willemsen, W Vaalburg
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Validation of S-1'-[18F]fluorocarazolol for in vivo imaging and quantification of cerebral beta-adrenoceptors.

S-1'-[18F]fluorocarazolol (S-(-)-4-(2-hydroxy-3-(1'-[18F]fluoroisopropyl)-aminopropoxy)carba zole, a non-subtype-selective beta-adrenoceptor antagonist) has been investigated for in vivo studies of beta-adrenoceptors. Previous results indicated that uptake of this radioligand in heart and lung can be inhibited by beta-adrenoceptor agonists and antagonists. In the present study, blocking, displacement and saturation experiments were performed in rats, in combination with metabolite analysis to investigate the suitability of this radioligand for in vivo positron emission tomography (PET) imaging and quantification of beta-adrenoceptors in the brain. The results demonstrate that, (i) the uptake of S-1'-[18F]fluorocarazolol reflects specific binding to beta-adrenoceptors, (ii) binding of S-1'-[18F]fluorocarazolol to atypical or non-beta-adrenergic sites is negligible, (iii) uptake of radioactive metabolites in the brain is less than 25% of total radioactivity, 60 min after injection, (iv) in vivo measurements of receptor densities (Bmax) in cortex, cerebellum, heart, lung and erythrocytes are within range of densities determined from in vitro assays, (v) binding of S-1'-[18F]fluorocarazolol can be displaced. In conclusion, S-1'-[18F]fluorocarazolol seems to possess the appropriate characteristics to visualize and quantify beta-adrenoceptors in vivo in the central nervous system using PET.

P Doze, A Van Waarde, P H Elsinga, A M Van-Loenen Weemaes, A T Willemsen, W Vaalburg
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Neurotransmitter positron emission tomographic-studies in adults with phenylketonuria, a pilot study.

Patients with phenylketonuria (PKU) may suffer from cognitive and neurological deficits which are related to reduced intracerebral concentrations of catecholamines. The function of phenylalanine (Phe) as an inhibitor of the uptake of the precursor amino acid tyrosine (Tyr) through the blood-brain barrier as well as an inhibitor of the expression of dopamine receptors in the brain is under investigation. Positron emission tomography (PET) is a method for quantitatively determining biochemical and physiological processes in vivo. In the current pilot study, L-[1-11C]-Tyr and 18F-fluoro-ethyl-spiperone (FESP) have been used. The metabolic pathway of carboxylic labelled Tyr is mainly incorporation into protein. From the measured tissue and plasma activity as a function of time in combination with a compartimental model the Protein Synthesis Rate (PSR) for Tyr can be calculated. FESP is a ligand which binds irreversibly to the dopamine D2-receptor and has also a low non specific binding, although affinity to the serotonin receptor has been described. The ratio of FESP concentration in striatum and in cerebellum is a measure of the receptor status in vivo. In patients with plasma Phe levels above the maximum therapeutic concentration (> 700 mumol/l) the PSR for Tyr was decreased as compared to controls and patients with plasma Phe concentrations within the therapeutic range, indicating a decreased availability of Tyr for neurotransmitter synthesis, and hence explaining the reduced cerebral concentration of catecholamines.

A M Paans, J Pruim, G P Smit, G Visser, A T Willemsen, K Ullrich
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