Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Quantification of P-glycoprotein function at the human blood-brain barrier using [ 18F]MC225 and PET.

INTRODUCTION: P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer's disease and Parkinson's disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[ 11C]verapamil PET. (R)-[ 11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [ 18F]MC225 was developed to measure both increases and decreases in P-gp function. AIM: The aim of this study was (1) to identify the pharmacokinetic model that best describes [ 18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. METHODS: Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [ 18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (V T), K i, and the rate constants K 1 and k 2). In addition, a reversible two-tissue compartment model with fixed k 3/k 4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. RESULTS: Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (V B) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the V T for [ 18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. CONCLUSION: [ 18F]MC225 V T, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. TRIAL REGISTRATION: EudraCT 2020-001564-28 . Registered 25 May 2020.</p

Rigorous Inequalities between Length and Time Scales in Glassy Systems

Glassy systems are characterized by an extremely sluggish dynamics without any simple sign of long range order. It is a debated question whether a correct description of such phenomenon requires the emergence of a large correlation length. We prove rigorous bounds between length and time scales implying the growth of a properly defined length when the relaxation time increases. Our results are valid in a rather general setting, which covers finite-dimensional and mean field systems. As an illustration, we discuss the Glauber (heat bath) dynamics of p-spin glass models on random regular graphs. We present the first proof that a model of this type undergoes a purely dynamical phase transition not accompanied by any thermodynamic singularity.Comment: 24 pages, 3 figures; published versio

Evaluation of P-glycoprotein function at the blood-brain barrier using [F-18]MC225-PET

P-glycoprotein (P-gp) is an ATP-dependent efflux transporter located at the blood–brain barrier (BBB), involved in the transport of a variety of neurotoxic substances out of the brain. Alterations in P-gp function play an essential role in the pathophysiological mechanisms underlying neurodegenerative disorders

On the freezing of variables in random constraint satisfaction problems

The set of solutions of random constraint satisfaction problems (zero energy groundstates of mean-field diluted spin glasses) undergoes several structural phase transitions as the amount of constraints is increased. This set first breaks down into a large number of well separated clusters. At the freezing transition, which is in general distinct from the clustering one, some variables (spins) take the same value in all solutions of a given cluster. In this paper we study the critical behavior around the freezing transition, which appears in the unfrozen phase as the divergence of the sizes of the rearrangements induced in response to the modification of a variable. The formalism is developed on generic constraint satisfaction problems and applied in particular to the random satisfiability of boolean formulas and to the coloring of random graphs. The computation is first performed in random tree ensembles, for which we underline a connection with percolation models and with the reconstruction problem of information theory. The validity of these results for the original random ensembles is then discussed in the framework of the cavity method.Comment: 32 pages, 7 figure

Local correlations in the 1D Bose gas from a scaling limit of the XXZ chain

We consider the K-body local correlations in the (repulsive) 1D Bose gas for general K, both at finite size and in the thermodynamic limit. Concerning the latter we develop a multiple integral formula which applies for arbitrary states of the system with a smooth distribution of Bethe roots, including the ground state and finite temperature Gibbs-states. In the cases K<=4 we perform the explicit factorization of the multiple integral. In the case of K=3 we obtain the recent result of Kormos et.al., whereas our formula for K=4 is new. Numerical results are presented as well.Comment: 23 pages, 2 figures, v2: minor modifications and references adde

EURECA: European-Japanese microcalorimeter array

The EURECA project aims to demonstrate technological readiness of a micro-calorimeter array for application in future X-ray astronomy missions, like Constellation-X, EDGE, and XEUS. The prototype instrument consists of a 5 × 5 pixel array of TES-based micro-calorimeters read out by two SQUID-amplifier channels using frequency-domain-multiplexing (FDM) with digital base-band feedback. The detector array is cooled by a cryogen-free cryostat consisting of a pulse tube cooler and a two stage ADR. Initial tests of the system at the PTB beam line of the BESSY synchrotron showed stable performance and an X-ray energy resolution of 1.5 eV at 250 eV for read-out of one TES-pixel only. Next step is deployment of FDM to read-out the full array. Full performance demonstration is expected end 2008.This work was financially supported by the Dutch Organization for Scientific Research (NWO).Peer Reviewe