Gunnar Blomquist

PET imaging of amyloid deposition in patients with mild cognitive impairment

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3+/-7.8 (S.D.) years) underwent PET studies with (11)C-PIB, and (18)F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1+/-6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps<0.01). The PIB retention in MCI converters was comparable to AD patients (p>0.01). Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively.

Evidence for astrocytosis in ALS demonstrated by [11C](L)-deprenyl-D2 PET.

OBJECTIVE To use deuterium-substituted [11C](L)-deprenyl PET to depict astrocytosis in vivo in patients with amyotrophic lateral sclerosis (ALS). BACKGROUND In human brain, the enzyme MAO-B is primarily located in astrocytes. L-deprenyl binds to MAO-B and autoradiography with 3H-L-deprenyl has been used to map astrocytosis in vitro. Motor neuron loss in ALS is accompanied by astrocytosis and astrocytes may play an active role in the neurodegenerative process. Deuterium-substituted [11C](L)-deprenyl PET provides an opportunity to localize astrocytosis in vivo in the brain of patients with ALS. METHODS Deuterium-substituted [11C](L)-deprenyl PET was performed in seven patients with ALS and seven healthy control subjects. RESULTS Increased uptake rate of [11C](L)-deprenyl was demonstrated in ALS in pons and white matter. CONCLUSION This study provides evidence that astrocytosis may be detected in vivo in ALS by the use of deuterium-substituted [11C](L)-deprenyl PET though further studies are needed to determine whether deuterium-substituted [11C](L)-deprenyl binding tracks disease progression and reflects astrocytosis.

Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood–brain barrier can be studied with PET

Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [(11)C]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [(11)C]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [(11)C]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [(11)C]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [(11)C]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [(11)C]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.

Unidirectional Influx and Net Accumulation of PIB.

The compound {N-methyl-[11C]}2-(4’-methylaminophenyl)-6-hydroxybenzothiazole, “PIB”, measured by positron emission tomography, has been demonstrated to image brain β-amyloid deposition in Alzheimer’s disease (AD). In the present study the benefit of measuring the PIB accumulation rate together with the unidirectional influx of PIB into the brain was investigated in healthy control subjects and patients with AD. In a monkey changes in the influx rate constant K1 of PIB closely followed changes in CBF, caused by alteration of PaCO2. In addition, K1 was high both in the monkey and in humans, suggesting that this parameter reflects CBF. Most AD patients studied showed clearly higher accumulation rate for PIB than the controls in cortical brain areas, while a few patients showed as low accumulation as the controls. K1 did not correlate with the accumulation rate, indicating that K1 for PIB provides extra information besides the accumulation rate.

Pharmacokinetics of P-glycoprotein inhibition in the rat blood-brain barrier

This article describes the experimental set-up and pharmacokinetic modeling of P-glycoprotein function in the rat blood-brain barrier using [(11)C]verapamil as the substrate and cyclosporin A as an inhibitor of P-gp. [(11)C]verapamil was administered to rats as an i.v. bolus dose followed by graded infusions to obtain steady-state concentrations in the brain during 70 min. CsA was administered as a bolus followed by a constant infusion 20 min after the start of the [(11)C]verapamil infusion. The brain uptake of [(11)C]verapamil over 2 h was portrayed in a sequence of PET scans in parallel with measurement of [(11)C]verapamil concentrations in blood and plasma and CsA concentrations in blood. Mixed effects modeling in NONMEM was used to build a pharmacokinetic model of CsA-induced P-gp inhibition. The brain pharmacokinetics of [(11)C]verapamil was well described by a two-compartment model. The effect of CsA on the uptake of [(11)C]verapamil in the brain was best described by an inhibitory indirect effect model with an effect on the transport of [(11)C]verapamil out of the brain. The CsA concentration required to obtain 50% of the maximal inhibition was 4.9 microg/mL (4.1 microM). The model parameters indicated that 93% of the outward transport of [(11)C]verapamil was P-gp mediated.

The use of PIB-PET as a dual pathological and functional biomarker in AD

Amyloid imaging with positron emission tomography (PET) is presently used in Alzheimers disease (AD) research. In this study we investigated the possibility to use early frames (ePIB) of the PIB scans as a rough index of CBF by comparing normalised early PIB values with cerebral glucose metabolism (rCMRglc). PIB-PET and FDG-PET were performed in 37 AD patients, 21 subjects with mild cognitive impairment (MCI) and 6 healthy controls (HC). The patients were divided based on their PIB retention (amyloid load) as either PIB positive (PIB+) or PIB negative (PIB-). Data of the unidirectional influx K(1) from a subset of the subjects including 7 AD patients and 3 HC was used for correlative analysis. Data was analysed using regions of interest (ROI) analysis. A strong, positive correlation was observed across brain regions between K(1) and ePIB (r=0.70; p≤0.001). The ePIB values were significantly lower in the posterior cingulate (p≤0.001) and the parietal cortices (p=0.002) in PIB+ subjects compared to PIB-, although the group difference were stronger for rCMRglc in cortical areas (p≤0.001). Strong positive correlations between ePIB and rCMRglc were observed in all cortical regions analysed, especially in the posterior cingulate and parietal cortices (p≤0.001). A single dynamic PIB-PET scan may provide information about pathological and functional changes (amyloidosis and impaired blood flow). This might be important for diagnosis of AD, enrichment of patients in clinical trials and evaluation of treatment effects. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Predicting brain concentrations of drug using positron emission tomography and venous input : modeling of arterial-venous concentration differences

ObjectiveIn a positron emission tomography (PET) study, the concentrations of the labeled drug (radiotracer) are often different in arterial and venous plasma, especially immediately following administration. In a PET study, the transfer of the drug from plasma to brain is usually described using arterial plasma concentrations, whereas venous sampling is standard in clinical pharmacokinetic studies of new drug candidates. The purpose of the study was to demonstrate the modeling of brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform (Tav).MethodsBrain kinetics (Cbr) was described as the convolution of arterial plasma kinetics (Car) with an arterial-to-brain impulse response function (Tbr). The arterial plasma kinetics was obtained as venous plasma kinetics (Cve) convolved with the inverse of the arterio-venous transform (Tav−1). The brain kinetics was then given by Cbr=Cve*Tav−1*Tbr. This concept was applied on data from a clinical PET study in which both arterial and venous plasma sampling was done in parallel to PET measurement of brain drug kinetics. The predictions of the brain kinetics based on an arterial input were compared with predictions using a venous input with and without an arterio-venous transform.ResultsThe venous based models for brain distribution, including a biexponential arterio-venous transform, performed comparably to models based on arterial data and better than venous based models without the transform. It was also shown that three different brain regions with different shaped concentration curves could be modeled with a common arterio-venous transform together with an individual brain distribution model.ConclusionWe demonstrated the feasibility of modeling brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform. Such a model can in turn be used for the calculation of brain kinetics resulting from an arbitrary administration mode by applying this model on venous plasma pharmacokinetics. This would be an important advantage in the development of drugs acting in the brain, and in other circumstances when the effect is likely to be closer related to the brain than the plasma concentration.

The central circulation in congestive heart failure non-invasively evaluated with dynamic positron emission tomography.

Background:  Positron emission tomography (PET) with [15O]‐H2O‐PET (WAT‐PET) or [11C]‐acetate (AC‐PET) quantifies myocardial perfusion and oxidative metabolism, but routine clinical use is hampered by the need for additional investigations to assess cardiac performance.

PET-Evaluated Transport of [11C]Hydroxyurea Across the Rat Blood-Brain Barrier - Lack of Influence of Cyclosporin and Probenecid

The transport of hydroxyurea, a ribonucleoside reductase inhibitor, over biological membranes is slow and it has therefore been suggested that the substance could interact with an active efflux transporter. The transport of [(11)C]hydroxyurea into the rat brain was therefore studied after administration of the multidrug resistance protein inhibitor probenecid (50 and 150 mg/kg), the P-glycoprotein inhibitor cyclosporin A (25 mg/kg), hydroxyurea (50, 150 and 450 mg/kg) and mannitol (25%). None of the intervention drugs affected the brain uptake of [(11)C]hydroxyurea. The brain-to-plasma concentration ratios (K(p)), with or without intervention drug, were in the range 0.12-0.25 after 60 min of [(11)C]hydroxyurea infusion. [(11)C]Verapamil, a P-glycoprotein substrate with low brain penetration, was used to study the ability of hydroxyurea to inhibit P-glycoprotein. Administration of hydroxyurea (150 and 450 mg/kg) did not increase brain concentrations of [(11)C]verapamil. It is therefore unlikely that hydroxyurea is a substrate for or an inhibitor of P-glycoprotein or a substrate for a probenecid sensitive transport system. The low brain concentrations may instead be the result of slow uptake due to the hydrophilic nature of hydroxyurea.

P2-303: Amyloid depositions in MCI-patients studied with PIB-PET

Anton Forsberg, Henry Engler, Gunnar Blomquist, Ove Almkvist, Göran Hagman, Anders Wall, Anna Ringheim, Bengt Långström, Agneta Nordberg, Karolinska Institutet, Neurotec Department, Stockholm, Sweden; Uppsala University Hospital, Uppsala, Sweden; Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden; Department of Geriatric Medicine Karolinska University Hospital Huddinge, Stockholm, Sweden; Uppsala Imanet AB, Imanet, GE Healthcare, Uppsala, Sweden; Department of Organic Chemistry, Uppsala University, Uppsala, Sweden. Contact e-mail: anton.forsberg@ki.se